81 results on '"Bridget A. Fernandez"'
Search Results
2. Genomic architecture of Autism Spectrum Disorder from comprehensive whole-genome sequence annotation
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Brett Trost, Bhooma Thiruvahindrapuram, Ada J.S. Chan, Worrawat Engchuan, Edward J. Higginbotham, Jennifer L. Howe, Livia O. Loureiro, Miriam S. Reuter, Delnaz Roshandel, Joe Whitney, Mehdi Zarrei, Matthew Bookman, Cherith Somerville, Rulan Shaath, Mona Abdi, Elbay Aliyev, Rohan V. Patel, Thomas Nalpathamkalam, Giovanna Pellecchia, Omar Hamdan, Gaganjot Kaur, Zhuozhi Wang, Jeffrey R. MacDonald, John Wei, Wilson W.L. Sung, Sylvia Lamoureux, Ny Hoang, Thanuja Selvanayagam, Nicole Deflaux, Melissa Geng, Siavash Ghaffari, John Bates, Edwin J. Young, Qiliang Ding, Carole Shum, Lia D’abate, Clarissa A. Bradley, Annabel Rutherford, Vernie Aguda, Beverly Apresto, Nan Chen, Sachin Desai, Xiaoyan Du, Matthew L.Y. Fong, Sanjeev Pullenayegum, Kozue Samler, Ting Wang, Karen Ho, Tara Paton, Sergio L. Pereira, Jo-Anne Herbrick, Richard F. Wintle, Jonathan Fuerth, Juti Noppornpitak, Heather Ward, Patrick Magee, Ayman Al Baz, Usanthan Kajendirarajah, Sharvari Kapadia, Jim Vlasblom, Monica Valluri, Joseph Green, Vicki Seifer, Morgan Quirbach, Olivia Rennie, Elizabeth Kelley, Nina Masjedi, Catherine Lord, Michael J. Szego, Ma’n H. Zawati, Michael Lang, Lisa J. Strug, Christian R. Marshall, Gregory Costain, Kristina Calli, Alana Iaboni, Afiqah Yusuf, Patricia Ambrozewicz, Louise Gallagher, David G. Amaral, Jessica Brian, Mayada Elsabbagh, Stelios Georgiades, Daniel S. Messinger, Sally Ozonoff, Jonathan Sebat, Calvin Sjaarda, Isabel M. Smith, Peter Szatmari, Lonnie Zwaigenbaum, Azadeh Kushki, Thomas W. Frazier, Jacob A.S. Vorstman, Khalid A. Fakhro, Bridget A. Fernandez, M.E. Suzanne Lewis, Rosanna Weksberg, Marc Fiume, Ryan K.C. Yuen, Evdokia Anagnostou, Neal Sondheimer, David Glazer, Dean M. Hartley, and Stephen W. Scherer
- Abstract
Fully understanding the genetic factors involved in Autism Spectrum Disorder (ASD) requires whole-genome sequencing (WGS), which theoretically allows the detection of all types of genetic variants. With the aim of generating an unprecedented resource for resolving the genomic architecture underlying ASD, we analyzed genome sequences and phenotypic data from 5,100 individuals with ASD and 6,212 additional parents and siblings (total n=11,312) in the Autism Speaks MSSNG Project, as well as additional individuals from other WGS cohorts. WGS data and autism phenotyping were based on high-quality short-read sequencing (>30x coverage) and clinically accepted diagnostic measures for ASD, respectively. For initial discovery of ASD-associated genes, we used exonic sequence-level variants from MSSNG as well as whole-exome sequencing-based ASD data from SPARK and the Autism Sequencing Consortium (>18,000 trios plus additional cases and controls), identifying 135 ASD-associated protein-coding genes with false discovery rate SCN2A and a nuclear mitochondrial insertion impacting SYNGAP1. Polygenic risk scores did not differ between children with ASD in multiplex families versus simplex, and rare, damaging recessive events were significantly depleted in multiplex families, collectively suggesting that rare, dominant variation plays a predominant role in multiplex ASD. Our study provides a guidebook for exploring genotype-phenotype correlations in the 15-20% of ASD families who carry ASD-associated rare variants, as well as an entry point to the larger and more diverse studies that will be required to dissect the etiology in the >80% of the ASD population that remains idiopathic. All data resulting from this study are available to the medical genomics research community in an open but protected manner.
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- 2022
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3. Genomic architecture of autism from comprehensive whole-genome sequence annotation
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Brett Trost, Bhooma Thiruvahindrapuram, Ada J.S. Chan, Worrawat Engchuan, Edward J. Higginbotham, Jennifer L. Howe, Livia O. Loureiro, Miriam S. Reuter, Delnaz Roshandel, Joe Whitney, Mehdi Zarrei, Matthew Bookman, Cherith Somerville, Rulan Shaath, Mona Abdi, Elbay Aliyev, Rohan V. Patel, Thomas Nalpathamkalam, Giovanna Pellecchia, Omar Hamdan, Gaganjot Kaur, Zhuozhi Wang, Jeffrey R. MacDonald, John Wei, Wilson W.L. Sung, Sylvia Lamoureux, Ny Hoang, Thanuja Selvanayagam, Nicole Deflaux, Melissa Geng, Siavash Ghaffari, John Bates, Edwin J. Young, Qiliang Ding, Carole Shum, Lia D'Abate, Clarrisa A. Bradley, Annabel Rutherford, Vernie Aguda, Beverly Apresto, Nan Chen, Sachin Desai, Xiaoyan Du, Matthew L.Y. Fong, Sanjeev Pullenayegum, Kozue Samler, Ting Wang, Karen Ho, Tara Paton, Sergio L. Pereira, Jo-Anne Herbrick, Richard F. Wintle, Jonathan Fuerth, Juti Noppornpitak, Heather Ward, Patrick Magee, Ayman Al Baz, Usanthan Kajendirarajah, Sharvari Kapadia, Jim Vlasblom, Monica Valluri, Joseph Green, Vicki Seifer, Morgan Quirbach, Olivia Rennie, Elizabeth Kelley, Nina Masjedi, Catherine Lord, Michael J. Szego, Ma'n H. Zawati, Michael Lang, Lisa J. Strug, Christian R. Marshall, Gregory Costain, Kristina Calli, Alana Iaboni, Afiqah Yusuf, Patricia Ambrozewicz, Louise Gallagher, David G. Amaral, Jessica Brian, Mayada Elsabbagh, Stelios Georgiades, Daniel S. Messinger, Sally Ozonoff, Jonathan Sebat, Calvin Sjaarda, Isabel M. Smith, Peter Szatmari, Lonnie Zwaigenbaum, Azadeh Kushki, Thomas W. Frazier, Jacob A.S. Vorstman, Khalid A. Fakhro, Bridget A. Fernandez, M.E. Suzanne Lewis, Rosanna Weksberg, Marc Fiume, Ryan K.C. Yuen, Evdokia Anagnostou, Neal Sondheimer, David Glazer, Dean M. Hartley, and Stephen W. Scherer
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DNA Copy Number Variations ,Autism Spectrum Disorder ,Humans ,Genetic Predisposition to Disease ,Genomics ,Autistic Disorder ,General Biochemistry, Genetics and Molecular Biology - Abstract
Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.
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- 2022
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4. Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
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Jacob A. S. Vorstman, Evdokia Anagnostou, Daniele Merico, Jeffrey R. MacDonald, Jennifer L. Howe, Zhuozhi Wang, Ryan K. C. Yuen, Thomas Nalpathamkalam, Judith H. Miles, Carol Negrijn, Miriam S. Reuter, Neal Sondheimer, Bridget A. Fernandez, Stephen W. Scherer, Wilson W L Sung, Kristiina Tammimies, Rohan V. Patel, Worrawat Engchuan, Giovanna Pellecchia, Nicole Takahashi, Mehdi Zarrei, Ada J.S. Chan, Dimitri J. Stavropoulos, Bhooma Thiruvahindrapuram, Sylvia Lamoureux, and Brett Trost
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Proband ,Genetics ,Autism spectrum disorder ,mental disorders ,medicine ,Intervention protocols ,Transmission disequilibrium test ,Biology ,medicine.disease ,Genome - Abstract
Defining different genetic subtypes of autism spectrum disorder (ASD) can enable the prediction of developmental outcomes. Based on minor physical and major congenital anomalies, we categorized 325 Canadian children with ASD into dysmorphic and nondysmorphic subgroups. We developed a method for calculating a patient-level, genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD had a significantly higher GRVS compared to those with nondysmorphic ASD (P= 0.027). Using the polygenic transmission disequilibrium test, we observed an over-transmission of ASD-associated common variants in nondysmorphic ASD probands (P= 2.9×10−3). These findings replicated using WGS data from 442 ASD probands with accompanying morphology data from the Simons Simplex Collection. Our results provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.
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- 2021
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5. Genome-wide detection of tandem DNA repeats expanded in autism
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Brett, Trost, Worrawat, Engchuan, Charlotte M, Nguyen, Bhooma, Thiruvahindrapuram, Egor, Dolzhenko, Ian, Backstrom, Mila, Mirceta, Bahareh A, Mojarad, Yue, Yin, Alona, Dov, Induja, Chandrakumar, Tanya, Prasolava, Natalie, Shum, Omar, Hamdan, Giovanna, Pellecchia, Jennifer L, Howe, Joseph, Whitney, Eric W, Klee, Saurabh, Baheti, David G, Amaral, Evdokia, Anagnostou, Mayada, Elsabbagh, Bridget A, Fernandez, Ny, Hoang, M E Suzanne, Lewis, Xudong, Liu, Calvin, Sjaarda, Isabel M, Smith, Peter, Szatmari, Lonnie, Zwaigenbaum, David, Glazer, Dean, Hartley, A Keith, Stewart, Michael A, Eberle, Nozomu, Sato, Christopher E, Pearson, Stephen W, Scherer, and Ryan K C, Yuen
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Male ,DNA Repeat Expansion ,Polymorphism, Genetic ,Autism Spectrum Disorder ,Genome, Human ,Intelligence ,Genomics ,Myotonin-Protein Kinase ,Article ,Fibroblast Growth Factors ,Tandem Repeat Sequences ,Iron-Binding Proteins ,Humans ,Female ,Genetic Predisposition to Disease ,Nucleotide Motifs - Abstract
Tandem DNA repeats vary by the size and sequence of each unit (motif). When expanded, they have been associated with >40 monogenic disorders(1). Their involvement in complex disorders is largely unknown, as is the extent of their heterogeneity. Here, we interrogated genome-wide characteristics of tandem repeats with 2-20 bp motifs in 17,231 genomes of families with autism(2,3) and population controls(4). We found extensive polymorphism in motif size and sequence. Many correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated tandem repeat expansions that were rare among population controls were significantly more prevalent among individuals with autism than their unaffected siblings, particularly in exons and near splice junctions and in genes related to nervous system development and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in autism-affected children versus 20.7% in unaffected children, suggesting a collective contribution to autism risk of 2.6%. They included novel autism-linked tandem repeat expansions in DMPK and FXN, known for neuromuscular conditions, and in novel loci such as FGF14 and CACNB1. These were associated with lower IQ and adaptive ability. Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic etiology and phenotypic complexity of autism.
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- 2020
6. PSE Interim Guidelines for Enhanced Quality and Safety at the Echocardiography Laboratory Amidst Emerging Infections - Summary Recommendations from the Task Force on Quality and Safety during Echocardiography of the Philippine Society of Echocardiography, Inc. and the Philippine Heart Association Council on Echocardiography (AN EXECUTIVE SUMMARY)
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Jose Donato A., Magno, primary, Mylene U., Cornel, additional, Jehan Karen G., Sumalpong, additional, Emmet Vi Ladlad, Pua, additional, Joyce S., Jumangit, additional, Rylan Jasper, Ubaldo, additional, Jonnie Bote, Nunez, additional, Patrick R., Carpo, additional, Aurora Muriel S., Gamponia, additional, Viannely Berywn F., Flores, additional, Aileen C., Senga, additional, Celia Catherine C., Uy, additional, Kristine Hashim, Bantala-Supnet, additional, Karla Rhea G., Rillera-Posadas, additional, Romeo J., Santos, additional, Victor L., Lazaro, additional, Gregorio G., Rogelio, additional, Stephanie Martha O., Obillos, additional, Ofelia N., Valencia, additional, Loewe O., Go, additional, Benjamin N., Alimurung, additional, Rosemarie, Ramirez-Ragasa, additional, Eugene B., Reyes, additional, Josephus R., Sibal, additional, Jose Jonas D., del Rosario, additional, Ma. Bridget D., Fernandez, additional, Myla Gloria S., Supe, additional, and Edwin S., Tucay, additional
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- 2020
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7. Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing
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Amanda C. Smith, Taila Hartley, Roberto Mendoza-Londono, J.S. Parboosingh, Bridget A. Fernandez, Jacek Majewski, Jeremy Schwartzentruber, Kym M. Boycott, Martine Tétreault, David A. Dyment, Chitra Prasad, Gabriella Horvath, Francois P. Bernier, Yanwei Xi, Asuri N. Prasad, Chandree L. Beaulieu, A.M. Innes, Christine M. Armour, C. A. Rupar, Eric Bareke, Lucie Dupuis, Ryan E. Lamont, Hugh J. McMillan, Tugce B. Balci, X.-R. Yang, and Julie Richer
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Male ,0301 basic medicine ,Proband ,Canada ,Pediatrics ,medicine.medical_specialty ,Genotype ,Genetic counseling ,Consanguinity ,Bioinformatics ,03 medical and health sciences ,Exome Sequencing ,Genetics ,Humans ,Medicine ,Family ,Genetic Predisposition to Disease ,Genetic Testing ,Clinical phenotype ,Genetic Association Studies ,Genetics (clinical) ,Exome sequencing ,Retrospective Studies ,Disease gene ,business.industry ,Siblings ,Genetic Diseases, Inborn ,Pedigree ,3. Good health ,Multisystem disease ,Phenotype ,030104 developmental biology ,Child, Preschool ,Mutation ,Dual diagnosis ,Female ,business - Abstract
Background Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. Aims We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. Materials & methods We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. Results Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. Conclusion Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.
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- 2017
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8. A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features
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Daniel R. Evans, Jane S. Green, Somayyeh Fahiminiya, Jacek Majewski, Bridget A. Fernandez, Matthew A. Deardorff, Gordon J. Johnson, James H. Whelan, Dirk Hubmacher, Suneel S. Apte, Care4Rare Canada Consortium, and Michael O. Woods
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Male ,Pathology ,medicine.medical_specialty ,Bodily Secretions ,Canada ,Population ,Mutation, Missense ,lcsh:Medicine ,Short stature ,Article ,Fingers ,ADAMTS Proteins ,Exome Sequencing ,Genetics research ,medicine ,Missense mutation ,Humans ,Ectopia lentis ,education ,lcsh:Science ,Exome sequencing ,education.field_of_study ,Multidisciplinary ,Anthropometry ,business.industry ,Brachydactyly ,lcsh:R ,Medical genetics ,Hereditary eye disease ,medicine.disease ,Weill–Marchesani syndrome ,Weill-Marchesani Syndrome ,Microspherophakia ,HEK293 Cells ,Phenotype ,lcsh:Q ,Female ,medicine.symptom ,business - Abstract
Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients’ hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.
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- 2020
9. A large data resource of genomic copy number variation across neurodevelopmental disorders
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Tara Goodale, Wendy Roberts, Jason P. Lerch, Bridget A. Fernandez, Melissa T. Carter, Vorstman Jas, Flanagan J, Bhooma Thiruvahindrapuram, Lonnie Zwaigenbaum, Jennifer Crosbie, Paul D. Arnold, Christian R. Marshall, Drmic I, Muhammad Faheem, Rohan V. Patel, Russell Schachar, Jennifer L. Howe, Kozue Samler, Stephen W. Scherer, Lu C, Rob Nicolson, Janet A. Buchanan, Edward J Higginbotham, Tara Paton, Mayada Elsabbagh, Chan Ajs, Stelios Georgiades, Peter Szatmari, Cheryl Cytrynbaum, Bahareh A. Mojarad, Daniele Merico, Sylvia Lamoureux, Evdokia Anagnostou, Barbara Kellam, Xudong Liu, Dimitri J. Stavropoulos, Christie L. Burton, Brett Trost, Ny Hoang, MacDonald, Young Ej, Anne S. Bassett, Heung T, Worrawat Engchuan, Wang X, Richard F. Wintle, Gregory A. Costain, Yuen Rkc, Marc Woodbury-Smith, Maian Roifman, Giovanna Pellecchia, Susan Walker, David R. Rosenberg, John Wei, Rosanna Weksberg, Mehdi Zarrei, Miron K, Wang T, Gregory L. Hanna, and Marsha Speevak
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0301 basic medicine ,medicine.medical_specialty ,lcsh:QH426-470 ,Microarray ,lcsh:Medicine ,Neurogenetics ,Pathogenesis ,Article ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Genetics ,medicine ,Attention deficit hyperactivity disorder ,Copy-number variation ,Molecular Biology ,Genetics (clinical) ,Molecular medicine ,business.industry ,lcsh:R ,Neurodevelopmental disorders ,medicine.disease ,3. Good health ,lcsh:Genetics ,030104 developmental biology ,Autism spectrum disorder ,Schizophrenia ,Etiology ,Medical genetics ,business ,030217 neurology & neurosurgery - Abstract
Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
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- 2019
10. Cardiac arrest in a mother and daughter and the identification of a novel RYR2 variant, predisposing to low penetrant catecholaminergic polymorphic ventricular tachycardia in a four-generation Canadian family
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Laura Arbour, Rick Leather, Bridget A. Fernandez, Matthew K. Tung, Ashley Collier, Kathy Hodgkinson, Sean Connors, Shubhayan Sanatani, Samantha Lauson, and Filip Van Petegem
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,lcsh:QH426-470 ,media_common.quotation_subject ,RYR2 ,Penetrance ,030105 genetics & heredity ,Catecholaminergic polymorphic ventricular tachycardia ,Ryanodine receptor 2 ,Variable Expression ,03 medical and health sciences ,Protein Domains ,Internal medicine ,Genetics ,medicine ,Humans ,crystallography ,Molecular Biology ,Index case ,Genetics (clinical) ,media_common ,Genetic testing ,Daughter ,medicine.diagnostic_test ,catecholaminergic polymorphic ventricular tachycardia ,Ryanodine receptor ,business.industry ,Ryanodine Receptor Calcium Release Channel ,Original Articles ,medicine.disease ,Heart Arrest ,Pedigree ,lcsh:Genetics ,030104 developmental biology ,variable expression ,Gain of Function Mutation ,Cardiology ,cardiovascular system ,Tachycardia, Ventricular ,Female ,Original Article ,business - Abstract
Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by adrenergically driven ventricular arrhythmia predominantly caused by pathogenic variants in the cardiac ryanodine receptor (RyR2). We describe a novel variant associated with cardiac arrest in a mother and daughter. Methods Initial sequencing of the RYR2 gene identified a novel variant (c.527G > T, p.R176L) in the index case (the mother), and her daughter. Structural analysis demonstrated the variant was located within the N‐terminal domain of RyR2, likely leading to a gain‐of‐function effect facilitating enhanced calcium ion release. Four generation cascade genetic and clinical screening was carried out. Results Thirty‐eight p.R176L variant carriers were identified of 94 family members with genetic testing, and 108 family members had clinical evaluations. Twelve carriers were symptomatic with previous syncope and 2 additional survivors of cardiac arrest were identified. Thirty‐two had clinical features suggestive of CPVT. Of 52 noncarriers, 11 had experienced previous syncope with none exhibiting any clinical features of CPVT. A documented arrhythmic event rate of 2.89/1000 person‐years across all carriers was calculated. Conclusion The substantial variability in phenotype and the lower than previously reported penetrance is illustrative of the importance of exploring family variants beyond first‐degree relatives., Here, we present a family study and structural analysis of a likely pathogenic RYR2 variant causing CPVT in a four‐generation Canadian family. If considering only the first‐degree relatives of our index case, the phenotype would seem to be highly penetrant and considered “severe.” However, with expanded, four‐generation genetic testing and clinical assessments (including 38 carriers of the variant) we show that the overall penetrance of the variant is low, illustrating the importance of exploring family variants beyond first‐degree relatives.
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- 2019
11. Familial Intracranial Aneurysm in Newfoundland: Clinical and Genetic Analysis
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Amy E. Powell, Barbara Noble, Bridget A. Fernandez, Falah B. Maroun, and Michael O. Woods
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Adult ,Male ,Newfoundland and Labrador ,Population ,Pilot Projects ,Disease ,Biology ,Genetic analysis ,symbols.namesake ,Humans ,Genetic Predisposition to Disease ,Family history ,education ,Exome sequencing ,Aged ,Genetics ,Sanger sequencing ,education.field_of_study ,Intracranial Aneurysm ,General Medicine ,Middle Aged ,Human genetics ,Pedigree ,Neurology ,Cohort ,symbols ,Female ,Neurology (clinical) - Abstract
Intracranial aneurysm (IA) is an expansion of the weakened arterial wall that is often asymptomatic until rupture, resulting in subarachnoid hemorrhage. Here we describe the high prevalence of familial IA in a cohort of Newfoundland ancestry. We began to investigate the genetic etiology of IA in affected family members, as the inheritance of this disease is poorly understood.Whole exome sequencing was completed for a cohort of 12 affected individuals from two multiplex families with a strong family history of IA. A filtering strategy was implemented to identify rare, shared variants. Filtered variants were prioritized based on validation by Sanger sequencing and segregation within the families.In family R1352, six variants passed filtering; while in family R1256, 68 variants remained, so further filtering was pursued. Following validation by Sanger sequencing, top candidates were investigated in a set of population controls, namely, C4orf6 c.A1G (p.M1V) and SPDYE4c.C103T (p.P35S). Neither was detected in 100 Newfoundland control samples.Rare and potentially deleterious variants were identified in both families, though incomplete segregation was identified for all filtered variants. Alternate methods of variant prioritization and broader considerations regarding the interplay of genetic and environmental factors are necessary in future studies of this disease.Prévalence d’anévrismes intracrâniens au sein de familles terre-neuviennes : une analyse clinique et génétique. Objectif : Un anévrisme intracrânien (AI) consiste en une expansion, souvent asymptomatique, d’une paroi artérielle affaiblie. La rupture qui peut s’ensuivre résultera en une hémorragie sous-arachnoïdienne. Nous voulons décrire ici la forte prévalence d’AI au sein de familles terre-neuviennes ayant des ancêtres communs. Nous avons débuté cette étude en étudiant l’étiologie génétique de l’AI chez les membres de ces familles affectés par cette déformation car l’hérédité des AI demeure encore mal comprise. Méthodes : Nous avons tout d’abord procédé au séquençage entier de l’exome d’un groupe de 12 sujets appartenant à deux familles dites « multiplexes » présentant des antécédents notables d’AI. À cet égard, une stratégie de filtrage a été mise de l’avant afin d’identifier des variantes génétiques à la fois peu fréquentes et partagées. Nous avons ensuite privilégié et validé ces variantes filtrées en nous fondant sur la méthode de séquençage et de ségrégation de Sanger. Résultats : Dans la famille R1352, 6 variantes ont été sélectionnées par filtrage alors que 68 variantes l’ont été dans le cas de la famille R1256, ce qui fait que des tâches additionnelles de filtrage ont été menées. Une fois complétée notre validation par la méthode de Sanger, les meilleurs sujets ont fait l’objet d’un travail d’analyse au sein d’un groupe de témoins de la population, à savoir C4orf6 c.A1G (p. M1V) et SPDYE4c.C103T (p. P35S). À cet égard, aucune variante génétique n’a été détectée parmi 100 échantillons de témoins de Terre-Neuve. Conclusion : Bien qu’une ségrégation incomplète ait été effectuée pour toutes les variantes filtrées, des variantes génétiques peu fréquentes et potentiellement délétères ont été détectées au sein de ces deux familles. D’autres méthodes de priorisation des variantes génétiques, de même que des considérations d’ordre plus général en ce qui a trait à l’interaction entre les facteurs génétiques et les facteurs environnementaux, sont nécessaires si l’on veut étudier les AI dans le futur.
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- 2019
12. Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees
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Jennifer L. Howe, Evdokia Anagnostou, Irene O'Connor, Veronica J. Vieland, Stephen W. Scherer, Jila Dastan, Marc Woodbury-Smith, Peter Szatmari, Andrew D. Paterson, Mehdi Zarrei, Bhooma Thiruvahindrapuram, Morgan Parlier, Ryan K. C. Yuen, Ann Thompson, Bridget A. Fernandez, Dimitri J. Stavropoulos, Joseph Piven, and John Wei
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Male ,genetic structures ,DNA Copy Number Variations ,Genotype ,Autism Spectrum Disorder ,Genetic Linkage ,DNA Mutational Analysis ,Gene Dosage ,Pedigree chart ,Nerve Tissue Proteins ,Biology ,behavioral disciplines and activities ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neurodevelopmental disorder ,Risk Factors ,mental disorders ,Gene duplication ,medicine ,Humans ,Genetic Predisposition to Disease ,Copy-number variation ,Autistic Disorder ,Child ,Gene ,Genetics (clinical) ,030304 developmental biology ,Genetics ,0303 health sciences ,Whole Genome Sequencing ,Infant ,medicine.disease ,Phenotype ,Pedigree ,Psychiatry and Mental health ,Autism spectrum disorder ,Child, Preschool ,Mutation ,Synapses ,Autism ,Female ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Autism spectrum disorder (ASD) is a relatively common childhood onset neurodevelopmental disorder with a complex genetic etiology. While progress has been made in identifying the de novo mutational landscape of ASD, the genetic factors that underpin the ASD's tendency to run in families are not well understood. In this study, nine extended pedigrees each with three or more individuals with ASD, and others with a lesser autism phenotype, were phenotyped and genotyped in an attempt to identify heritable copy number variants (CNVs). Although these families have previously generated linkage signals, no rare CNV segregated with these signals in any family. A small number of clinically relevant CNVs were identified. Only one CNV was identified that segregated with ASD phenotype; namely, a duplication overlapping DLGAP2 in three male offspring each with an ASD diagnosis. This gene encodes a synaptic scaffolding protein, part of a group of proteins known to be pathologically implicated in ASD. On the whole, however, the heritable nature of ASD in the families studied remains poorly understood.
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- 2019
13. Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss
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Jessica Squires, Justin A. Pater, Terry-Lynn Young, Jiayi Zhou, Nicole M. Roslin, Sara Fernandez, Taylor Burt, Bridget A. Fernandez, Anne Griffin, Jane Green, Jim Houston, and Darren D. O’Rielly
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0301 basic medicine ,Retinal degeneration ,Male ,lcsh:Internal medicine ,Pediatrics ,medicine.medical_specialty ,lcsh:QH426-470 ,RNA splicing ,Genotype ,Hearing loss ,Usher syndrome ,media_common.quotation_subject ,Nonsense ,030105 genetics & heredity ,Knowledge translation ,03 medical and health sciences ,Deaf-Blind Disorders ,Retinitis pigmentosa ,Genetics ,medicine ,otorhinolaryngologic diseases ,Humans ,lcsh:RC31-1245 ,Child ,Genetics (clinical) ,Exome sequencing ,Genetic isolate ,media_common ,Syndromic hearing loss ,business.industry ,Cytogenetics ,Whole exome sequencing ,medicine.disease ,Human genetics ,3. Good health ,Pedigree ,lcsh:Genetics ,030104 developmental biology ,Phenotype ,Child, Preschool ,Female ,medicine.symptom ,business ,Usher Syndromes ,Research Article - Abstract
Background Usher syndrome, the most common form of inherited deaf-blindness, is unlike many other forms of syndromic hereditary hearing loss in that the extra aural clinical manifestations are also detrimental to communication. Usher syndrome patients with early onset deafness also experience vision loss due to progressive retinitis pigmentosa that can lead to legal blindness in their third or fourth decade. Methods Using a multi-omic approach, we identified three novel pathogenic variants in two Usher syndrome genes (USH2A and ADGRV1) in cases initially referred for isolated vision or hearing loss. Results In a multiplex hearing loss family, two affected sisters, the product of a second cousin union, are homozygous for a novel nonsense pathogenic variant in ADGRV1 (c.17062C > T, p.Arg5688*), predicted to create a premature stop codon near the N-terminus of ADGRV1. Ophthalmological examination of the sisters confirmed typical retinitis pigmentosa and prompted a corrected Usher syndrome diagnosis. In an unrelated clinical case, a child with hearing loss tested positive for two novel USH2A splicing variants (c.5777-1G > A, p. Glu1926_Ala1952del and c.10388-2A > G, p.Asp3463Alafs*6) and RNA studies confirmed that both pathogenic variants cause splicing errors. Interestingly, these same USH2A variants are also identified in another family with vision loss where subsequent clinical follow-up confirmed pre-existing hearing loss since early childhood, eventually resulting in a reassigned diagnosis of Usher syndrome. Conclusion These findings provide empirical evidence to increase Usher syndrome surveillance of at-risk children. Given that novel antisense oligonucleotide therapies have been shown to rescue retinal degeneration caused by USH2A splicing pathogenic variants, these solved USH2A patients may now be eligible to be enrolled in therapeutic trials.
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- 2019
14. Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach
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Bridget A. Fernandez and Stephen W. Scherer
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Male ,DNA Copy Number Variations ,Autism Spectrum Disorder ,syndromic ,behavioral disciplines and activities ,ASD-risk gene ,whole exome sequencing ,Fragile X Mental Retardation Protein ,Clinical Research ,mental disorders ,Humans ,copy number variant ,Female ,Genetic Predisposition to Disease ,microarray ,Genetic Association Studies - Abstract
Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions diagnosed solely on the basis of behavioral assessments that reveal social deficits. Progress has been made in understanding its genetic underpinnings, but most ASD-associated genetic variants, which include copy number variants (CNVs) and mutations in ASD-risk genes, account for no more than 1 % of ASD cases. This high level of genetic heterogeneity leads to challenges obtaining and interpreting genetic testing in clinical settings. The traditional definition of syndromic ASD is a disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. Most have a known genetic cause. Examples include fragile X syndrome and tuberous sclerosis complex. We propose dividing syndromic autism into the following two groups: (i) ASD that occurs in the context of a clinically defined syndrome-recognizing these disorders depends on the familiarity of the clinician with the features of the syndrome, and the diagnosis is typically confirmed by targeted genetic testing (eg, mutation screening of FMR1); (ii) ASD that occurs as a feature of a molecularly defined syndrome-for this group of patients, ASD-associated variants are identified by genome-wide testing that is not hypothesis driven (eg, microarray, whole exome sequencing). These ASD groups cannot be easily clinically defined because patients with a given variant have variable somatic abnormalities (dysmorphism and birth defects). In this article, we review common diagnoses from the above categories and suggest a testing strategy for patients, guided by determining whether the individual has essential or complex ASD; patients in the latter group have multiple morphologic anomalies on physical examination. Finally, we recommend that the syndromic versus nonsyndromic designation ultimately be replaced by classification of ASD according to its genetic etiology, which will inform about the associated spectrum and penetrance of neurobehavioral and somatic manifestations.El trastorno del espectro autista (TEA) incluye un grupo diverso de cuadros del neurodesarrollo, diagnosticado por los clínicos únicamente en base a evaluaciones conductuales que revelan déficits sociales. Se ha progresado en la comprensión de sus bases genéticas, pero la mayoría de las variantes genéticas asociadas al TEA dan cuenta de no más del 1 % de los casos, y éstas incluyen variabilidad del número de copias (VNC) y mutaciones en los genes de riesgo para el TEA. Este alto nivel de heterogeneidad genética genera un desafío en la obtención e interpretación de las pruebas genéticas en los ambientes clínicos. La definición tradicional de TEA sindromático se refiere a un trastorno con un patrón clínicamente definido de alteraciones somáticas y un fenotipo neuroconductual que incluye el TEA. La mayoría tiene una causa genéticamente conocida y como ejemplos están el síndrome X frágil y el complejo esclerosis tuberosa. Se propone dividir el autismo sindromático en dos grupos: 1) El TEA que ocurre en el contexto de un síndrome definido clínicamente. El reconocimiento de estos trastornos depende de la familiaridad del clínico con las características del síndrome, y el diagnóstico se confirma típicamente por pruebas genéticas específicas (como la evaluación de FMR1) y 2) El TEA que ocurre como una característica del síndrome definido molecularmente. Para este grupo de pacientes, las variantes asociadas con el TEA se identifican mediante pruebas del genoma completo, que no se basan en una hipótesis (como el estudio de microarray o la secuenciación completa de exoma). Estos grupos de TEA no pueden definirse fácil clínicamente porque los pacientes con una variante determinada tienen alteraciones somáticas variables (dimorfismos y defectos del nacimiento). En este artículo se revisan los diagnósticos comunes a partir de las categorías anteriores y se sugiere una estrategia de evaluación de los pacientes dependiendo de si ellos tienen un TEA esencial o complejo; este último grupo tiene múltiples alteraciones morfológicas al examen físico. Por último, se recomienda que la designación de sindromático versus no-sindromático sea reemplazada finalmente por la clasificación de TEA de acuerdo con su etiología genética, la cual dará cuenta del espectro asociado y de la penetrancia de las manifestaciones neuroconductuales y somáticas.Le trouble du spectre de l'autisme (TSA) est un groupe de maladies neurodéveloppementales dont le diagnostic est établi uniquement sur la base d'évaluations comportementales qui signent des déficits sociaux. La compréhension des fondements génétiques du TSA progresse, mais la plupart des variantes génétiques associées au TSA, comme la variabilité du nombre de copies (VNC) et les mutations des gènes liés au TSA, ne représentent pas plus de 1 % des cas de TSA. Cette hétérogénéité génétique élevée rend difficiles la réalisation et l'interprétation des dépistages génétiques en milieu clinique. La définition traditionnelle du TSA syndromique est un tableau clinique défini, composé d'anomalies somatiques associées à un phénotype neurocomportemental pouvant comprendre le TSA. La plupart ont une cause génétique connue, comme le syndrome de l'X fragile et la sclérose tubéreuse complexe. Nous proposons de diviser l'autisme syndromique en deux groupes : 1) le TSA survenant dans le contexte d'un syndrome cliniquement défini - la reconnaissance de ces troubles dépend de la connaissance du médecin des caractéristiques du syndrome, et le diagnostic est confirmé généralement par des tests génétiques ciblés (par exemple le dépistage d'une mutation du gène FMR1) ; 2) le TSA survenant en tant que caractéristique d'un syndrome moléculairement défini - pour ce groupe de patients, les variantes associées au TSA sont identifiées par un dépistage au niveau du génome entier sans a priori (par exemple puces à ADN, séquençage de l'exome entier). Ces groupes de TSA ne sont pas faciles à définir cliniquement car les patients ayant une variante donnée ont des anomalies somatiques variables (dysmorphisme et anomalies congénitales). Dans cet article, nous examinons les diagnostics courants issus des catégories susmentionnées et suggérons une stratégie de dépistage pour les patients, pour déterminer si leur TSA est essentiel ou complexe, ce dernier groupe ayant des anomalies morphologiques multiples à l'examen clinique. Enfin, nous recommandons que la classification syndromique versus non syndromique soit finalement remplacée par une classification du TSA selon son étiologie génétique, qui renseignera sur le spectre et la pénétrance des manifestations neuro-comportementales et somatiques.
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- 2017
15. A genome-wide linkage study of autism spectrum disorder and the broad autism phenotype in extended pedigrees
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Marc Woodbury-Smith, Jennifer L. Howe, Ryan K. C. Yuen, Peter Szatmari, Ann Thompson, Joseph Piven, Irene O'Connor, Morgan Parlier, Andrew D. Paterson, Veronica J. Vieland, Stephen W. Scherer, Bridget A. Fernandez, and Mehdi Zarrei
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Male ,0301 basic medicine ,Autism Spectrum Disorder ,Genetic Linkage ,Pedigree chart ,Family genetics ,0302 clinical medicine ,Child ,Aged, 80 and over ,Genome-wide linkage ,Genetics ,Middle Aged ,Autism spectrum disorder (ASD) ,Pedigree ,3. Good health ,Phenotype ,Autism spectrum disorder ,Child, Preschool ,Female ,Allelic heterogeneity ,Adult ,Canada ,Adolescent ,Cognitive Neuroscience ,Locus (genetics) ,Biology ,behavioral disciplines and activities ,Chromosomes ,White People ,lcsh:RC321-571 ,Pathology and Forensic Medicine ,Young Adult ,03 medical and health sciences ,Genetic linkage ,mental disorders ,medicine ,Humans ,Posterior probability of linkage (PPL) ,Genetic Predisposition to Disease ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Aged ,Research ,Infant ,Bayes Theorem ,medicine.disease ,United States ,Human genetics ,030104 developmental biology ,Pediatrics, Perinatology and Child Health ,Autism ,Neurology (clinical) ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Extended pedigrees - Abstract
Background Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees. Methods ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale. Results The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent. Conclusions Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity. Electronic supplementary material The online version of this article (10.1186/s11689-018-9238-9) contains supplementary material, which is available to authorized users.
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- 2018
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16. Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care
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Gail E. Graham, David A. Dyment, Chandree L. Beaulieu, Sara L. Sawyer, Mark A. Tarnopolsky, Jane Green, Patrick Frosk, Julie Richer, Victoria Mok Siu, Constantin Polychronakos, Jacques L. Michaud, Francois P. Bernier, Mark E. Samuels, A.M. Innes, Ordan J. Lehmann, Michael T. Geraghty, Taila Hartley, Dennis E. Bulman, Jacek Majewski, Gabriella Horvath, Guy A. Rouleau, Geneviève Bernard, Sarah M. Nikkel, Farah R. Zahir, Aneal Khan, Amanda C. Smith, H M Bedford, Elise Héon, Johnny Deladoëy, Robert M. Gow, L S Penney, Kym M. Boycott, William T. Gibson, Oksana Suchowersky, Bridget A. Fernandez, Roberto Mendoza-Londono, Jeremy Schwartzentruber, Brenda Gerull, Raymond H. Kim, Robert K. Koenekoop, Bernard Brais, Grace Yoon, David Chitayat, Nada Jabado, and J. Warman Chardon
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0301 basic medicine ,Canada ,Reviews ,Disease ,Review ,Bioinformatics ,Novel gene ,03 medical and health sciences ,Genetics ,Medicine ,Humans ,Exome ,clinical exome ,Child ,Genetics (clinical) ,Exome sequencing ,Disease gene ,business.industry ,Genetic heterogeneity ,Genetic Diseases, Inborn ,rare diseases ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,FORGE Canada Consortium ,3. Good health ,030104 developmental biology ,Genes ,Clinical diagnosis ,Mutation ,whole‐exome sequencing ,business ,Rare disease - Abstract
An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.
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- 2015
17. Incidence and cohort prevalence for autism spectrum disorders in the Avalon Peninsula, Newfoundland and Labrador
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Bridget A. Fernandez, Leigh Anne Newhook, Cathy Vardy, Roger Chafe, and Lorine Pelly
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High rate ,education.field_of_study ,Pediatrics ,medicine.medical_specialty ,Rehabilitation ,business.industry ,Research ,medicine.medical_treatment ,Incidence (epidemiology) ,Population ,Prospective data ,General Medicine ,medicine.disease ,Autism spectrum disorder ,Cohort ,medicine ,Autism ,business ,education - Abstract
Background: Recent studies have reported increased prevalence for autism spectrum disorders in a number of geographical locations. Our objective was to determine the incidence and 1-year cohort prevalence for autism spectrum disorders in children less than 15 years of age and living in the Avalon Peninsula at the time of diagnosis. Methods: Retrospective and prospective data were obtained from the Janeway Children’s Health and Rehabilitation Centre (St. John’s), including the identification and specific diagnosis for all children assessed for autism spectrum disorder from 2006 to 2010. Additional clinic data were reviewed to update the data until the end of 2013. Results: From 2006 to 2010, 272 children had a diagnosis of autism spectrum disorder, averaging 54 new cases per year. The incidence of new cases increased from 10.1 to 16.7 cases per 10 000 per year from 2006 to 2010. At the end of 2013, the prevalence among children born in 2006 was 1 case of autism spectrum disorder per 46 children or 215.77 per 10 000. Interpretation: We found higher rates of autism spectrum disorder than previously reported for this population. The prevalence in this region is also high when compared with other global populations. The high rate of diagnosis supports the need for a provincial autism spectrum disorder registry and further research on autism spectrum disorder within this population.
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- 2015
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18. Whole-genome sequencing of quartet families with autism spectrum disorder
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Rosanna Weksberg, Bhooma Thiruvahindrapuram, Matthew J. Gazzellone, Robert H. Ring, Lonnie Zwaigenbaum, Mehdi Zarrei, Ryan K. C. Yuen, Peter Szatmari, Bridget A. Fernandez, Jennifer L. Howe, Christina Chrysler, Susan Walker, Daniele Merico, Kristiina Tammimies, Ann Thompson, Lia D’Abate, Mohammed Uddin, Ny Hoang, Richard S C Liu, Giovanna Pellecchia, Yi Liu, Melissa T. Carter, Wendy Roberts, Eric Deneault, Stephen W. Scherer, Christian R. Marshall, Peter N. Ray, and Thomas Nalpathamkalam
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Adult ,Male ,Parents ,Sequence analysis ,Biology ,behavioral disciplines and activities ,Genome ,General Biochemistry, Genetics and Molecular Biology ,mental disorders ,Genetic variation ,medicine ,Humans ,Genetic Predisposition to Disease ,Child ,Gene ,Genetics ,Whole genome sequencing ,Genetic heterogeneity ,Siblings ,Sequence Analysis, DNA ,General Medicine ,medicine.disease ,Phenotype ,Child Development Disorders, Pervasive ,Autism spectrum disorder ,Female - Abstract
Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics.
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- 2015
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19. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia
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Geraldine Dawson, Sven Sandin, Frederico Duque, Peter Holmans, Marion Leboyer, Aarno Palotie, Fritz Poustka, Richard Delorme, Stephen Sanders, Alistair T. Pagnamenta, Lonnie Zwaigenbaum, Bridget A. Fernandez, A. Jeremy Willsey, Christine M. Freitag, Christa Lese Martin, Elena Maestrini, Elena Bacchelli, Guiomar Oliveira, Jeremy R. Parr, Guy A. Rouleau, Jonas Bybjerg-Grauholm, Joseph Piven, Latha Soorya, Lauren A. Weiss, Jonathan Green, Carsten Bøcker Pedersen, Louise Gallagher, Regina Regan, Stephan Ripke, Thomas Werge, Pat Levitt, Aravinda Chakravarti, Joana Almeida, Kathryn Roeder, Catalina Betancur, Bernie Devlin, Benjamin M. Neale, Gillian Baird, Jakob Grove, Thomas Bourgeron, David H. Ledbetter, Eftichia Duketis, Karola Rehnström, Gerard D. Schellenberg, Jillian P. Casey, Preben Bo Mortensen, Patrick Bolton, Igor Martsenkovsky, Elise Robinson, Hakon Hakonarson, Vanessa H. Bal, Stacy Steinberg, Christopher Gillberg, Kathryn Tsang, Jacob A. S. Vorstman, Verneri Anttila, Suma Jacob, Judith Conroy, J. Haines, William M. McMahon, Edwin H. Cook, Ann P. Thompson, Inês C. Conceição, Mark J. Daly, Arthur P. Goldberg, Sarah E. Medland, Milica Pejovic-Milovancevic, David M. Hougaard, Shrikant Mane, Christina M. Hultman, Susana Mouga, Hreinn Stefansson, Ellen M. Wijsman, Andreas G. Chiocchetti, Ole Mors, Phil Lee, Richard Anney, Astrid M. Vicente, Veronica J. Vieland, K. Stefansson, Stephen W. Scherer, Teimuraz Silagadze, Pall Magnusson, Donna M. Martin, Merete Nordentoft, Peter Szatmari, Patrícia B. S. Celestino-Soper, Ann S Le-Couteur, Cátia Café, Arthur L. Beaudet, Kerstin Wittemeyer, Anders D. Børglum, Joel S. Bader, Christopher S. Poultney, Hailiang Huang, Alexander Kolevzon, Margaret A. Pericak-Vance, Joachim Hallmayer, Rita M. Cantor, Eric Fombonne, Andrew Green, Dan E. Arking, M. Daniele Fallin, Matthew W. State, Christine Ladd-Acosta, Silvia Derubeis, Raphael Bernier, Regina Waltes, David G. Amaral, Manuel Mattheisen, Abraham Reichenberg, Lambertus Klei, Daniel Moreno-De-Luca, Marie Bækvad-Hansen, Maretha V. Dejonge, Susan G. McGrew, Joseph D. Buxbaum, Hilary Coon, Jennifer Reichert, Michael Gill, Herman Vanengeland, Christine Søholm Hansen, Anthony P. Monaco, Nadia Bolshakova, John I. Nurnberger, Nancy J. Minshew, Michael T. Murtha, Thomas H. Wassink, Evald Saemundsen, Simon Wallace, Sean Brennan, Sean Ennis, A. Gulhan Ercan-Sencicek, Sven Bölte, Oscar Svantesson, Susan L. Santangelo, Andrew D. Paterson, Robert L. Hendren, Timothy W. Yu, Dalila Pinto, D.E. Grice, Alison Merikangas, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, Christopher A. Walsh, Susan E. Folstein, Wendy Roberts, Sabine M. Klauck, Marianne Giørtz Pedersen, Tiago R. Magalhaes, John R. Gilbert, Irva Hertz-Picciotto, James S. Sutcliffe, Evdokia Anagnostou, Catarina Correia, Eric M. Morrow, Daniel H. Geschwind, Jennifer K. Lowe, Agatino Battaglia, Bozenna Iliadou, Michael L. Cuccaro, Catherine Lord, MRC Centre for Neuropsychiatric Genetics and Genomics [Cardiff, UK], Cardiff University, The Autism Working Group of the Psychiatric Genomics Consortium was supported by National Institutes of Mental Health (NIMH, USA) grant MH109539, MH094432 and MH094421 to M.J.D. The ACE Network was supported by MH081754 and MH100027 to D.H.G. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) and was supported by grant MH081810. The Autism Genome Project (AGP) was supported by grants from Autism Speaks, the Canadian Institutes of Health Research (CIHR), Genome Canada, the Health Research Board (Ireland, AUT/ 2006/1, AUT/2006/2, PD/2006/48), the Hilibrand Foundation (USA), the Medical Research Council (UK), the National Institutes of Health (USA, the National Institute of Child Health and Human Development and the National Institute of Mental Health), the Ontario Genomics Institute, and the University of Toronto McLaughlin Centre. The Simons Simplex Collection (SSC) was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the Simons Simplex Collection Genetic Consortium), approved researchers can obtain the SSC population dataset described in this study (http://sfari.org/resources/sfari-base) by applying at https://base.sfari.org. The Gene Discovery Project of Johns Hopkins was funded by MH060007, MH081754, and the Simons Foundation. The MonBos Collection study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample (part of the MonBos collection) was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. The PAGES collection was funded by NIMH grant MH097849. The collection of data and biomaterials that participated in the NIMH Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219, and MH00980, National Health Medical Research Council grant 0034328, and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford), and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The iPSYCH project is funded by The Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. In addition, the genotyping of iPSYCH samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432-02 to MJD). The Study to Explore Early Development (SEED) was funded by the Centers for Disease Control and Prevention (CDC) grants U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, and U10DD000498. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Additional statistical analyses were performed and supported by the Trinity Centre for High Performance Computing (http://www.tchpc.tcd.ie/) funded through Science Foundation Ireland. Computational support for the PAGES collection was provided in part through the computational resources and staff expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (https://hpc.mssm.edu). Data QC and statistical analyses of the iPSYCH samples were performed at the high-performance computing cluster GenomeDK (http://genome.au.dk) at the Center for Integrative Sequencing, iSEQ, Aarhus University. iSEQ provided computed time, data storage, and technical support for the study., Richard JL Anney, Email: anneyr@cardiff.ac.uk, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK, Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Stephan Ripke, Email: ripke@atgu.mgh.harvard.edu, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany. Verneri Anttila, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Jakob Grove, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, DK-8000, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark, Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. Peter Holmans, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK. Hailiang Huang, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lambertus Klei, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Phil H Lee, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA. Sarah E Medland, Affiliation/s: Queensland Institute of Medical Research Brisbane, QLD, 4006, Australia. Benjamin Neale, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Elise Robinson, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lauren A Weiss, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Lonnie Zwaigenbaum, Affiliation/s: Department of Pediatrics, University of Alberta, Edmonton, AB, T6G 1C9, Canada. Timothy W Yu, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Kerstin Wittemeyer, Affiliation/s: School of Education, University of Birmingham, Birmingham, B15 2TT, UK. A.Jeremy Willsey, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Ellen M Wijsman, Affiliation/s: Department of Medicine, University of Washington, Seattle, WA 98195, USA, Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Thomas Werge, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Institute of Biological Psychiatry, MHC Sct Hans, Mental Health Services Copenhagen, Roskilde, Denmark, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK-2200, Denmark. Thomas H Wassink, Affiliation/s: Department of Psychiatry, Carver College of Medicine, Iowa City, IA 52242, USA. Regina Waltes, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher A Walsh, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA, Program in Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA, Simon Wallace, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK. Jacob AS Vorstman, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Veronica J Vieland, Affiliation/s: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children ’ s Hospital, Columbus, OH 43205, USA. Astrid M Vicente, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Herman vanEngeland, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Kathryn Tsang, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Ann P Thompson, Affiliation/s: Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, L8S 4L8, Canada. Peter Szatmari, Affiliation/s: Department of Psychiatry, University of Toronto, ON, M5T 1R8, Canada. Oscar Svantesson, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stacy Steinberg, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Kari Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Hreinn Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Matthew W State, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Latha Soorya, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, USA. Teimuraz Silagadze, Affiliation/s: Department of Psychiatry and Drug Addiction, Tbilisi State Medical University, Tbilisi, 0186, Georgia. Stephen W Scherer, Affiliation/s: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, McLaughlin Centre, University of Toronto, Toronto, ON, M5G 0A4, Canada, Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. Gerard D Schellenberg, Affiliation/s: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA. Sven Sandin, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stephan J Sanders, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Evald Saemundsen, Affiliation/s: State Diagnostic and Counseling Centre, Kopavogur, IS-201, Iceland. Guy A Rouleau, Affiliation/s: Montreal Neurological Institute, Dept of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada. Bernadette Rogé, Affiliation/s: Centre d ’ Etudes et de Recherches en Psychopathologie, Toulouse University, Toulouse, 31058, France. Kathryn Roeder, Affiliation/s: Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA, Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. Wendy Roberts, Affiliation/s: Autism Research Unit, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada. Jennifer Reichert, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Abraham Reichenberg, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Karola Rehnström, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK. Regina Regan, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Fritz Poustka, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher S Poultney, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Joseph Piven, Affiliation/s: University of North Carolina, Chapel Hill, NC 27599, USA. Dalila Pinto, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Margaret A Pericak-Vance, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Milica Pejovic-Milovancevic, Affiliation/s: Institute of Mental Health and Medical Faculty, University of Belgrade, Belgrade, 11 000, Serbia. Marianne Giørtz Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, National Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Carsten Bøcker Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Andrew D Paterson, Affiliation/s: Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, Dalla Lana School of Public Health, Toronto, ON, M5T 3M7, Canada. Jeremy R Parr, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Alistair T Pagnamenta, Affiliation/s: Wellcome Trust Centre for Human Genetics, OxfordUniversity,Oxford,OX37BN,UK. Guiomar Oliveira, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. John I Nurnberger, Affiliation/s: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Merete Nordentoft, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. Michael T Murtha, Affiliation/s: Programs on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA. Susana Mouga, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Preben Bo Mortensen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Na- tional Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark, Ole Mors, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. Eric M Morrow, Affiliation/s: Department of Psychiatry and Human Behaviour, Brown University, Providence, RI 02912, USA. Daniel Moreno-De-Luca, Affiliation/s: Department of Psychiatry and Hu- man Behaviour, Brown University, Providence, RI 02912, USA. Anthony P Monaco, Affiliation/s: Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK, Tufts University, Boston, MA 02155?, USA. Nancy Minshew, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Alison Merikangas, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. William M McMahon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Susan G McGrew, Affiliation/s: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA. Manuel Mattheisen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Igor Martsenkovsky, Affiliation/s: Department of Child, Adolescent Psychiatry and Medical-Social Rehabilitation, Ukrainian Research Institute of Social Fo- rensic Psychiatry and Drug Abuse, Kyiv, 04080, Ukraine. Donna M Martin, Affiliation/s: Department of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Shrikant M Mane, Affiliation/s: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06516, USA. Pall Magnusson, Affiliation/s: Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, IS-101, Iceland. Tiago Magalhaes, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Elena Maestrini, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Jennifer K Lowe, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Catherine Lord, Affiliation/s: Department of Psychiatry, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Pat Levitt, Affiliation/s: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. Christa LeseMartin, Affiliation/s: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, PA 17837, USA. David H Ledbetter, Affiliation/s: Chief Scientific Officer, Geisinger Health System, Danville, PA 17837, USA. Marion Leboyer, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, INSERM U955, Paris, 94010, France, Faculté de Médecine, Université Paris Est, Créteil, 94000, France, Department of Psychiatry, Henri Mondor-Albert Chene- vier Hospital, Assistance Publique – Hôpitaux de Paris, Créteil, 94000, France, Ann S LeCouteur, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Christine Ladd-Acosta, Affiliation/s: Department of Epidemiology, Johns Hop- kins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Alexander Kolevzon, Affiliation/s: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Sabine M Klauck, Affiliation/s: Division of Molecular Genome Analysis and Working Group Cancer Genome Research, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany. Suma Jacob, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA, Institute of Translational Neuroscience and Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA. Bozenna Iliadou, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Christina M Hultman, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. David M Hougaard, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Irva Hertz-Picciotto, Affiliation/s: Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA, The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA. Robert Hendren, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Christine Søholm Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Jonathan L Haines, Affiliation/s: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Stephen J Guter, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Dorothy E Grice, Affiliation/s: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Jonathan M Green, Affiliation/s: Manchester Academic Health Sciences Centre, Manchester, M13 9NT, UK, Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, M13 9PT, UK. Andrew Green, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Arthur P Goldberg, Affiliation/s: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Christopher Gillberg, Affiliation/s: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, S-405 30, Sweden. John Gilbert, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Louise Gallagher, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Christine M Freitag, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Eric Fombonne, Affiliation/s: Department of Psychiatry and Institute for Development and Disability, Oregon Health and Science University, Portland, OR 97239, USA. Susan E Folstein, Affiliation/s: Division of Child and Adolescent Psychiatry, Department of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Bridget Fernandez, Affiliation/s: Memorial University of Newfoundland, St John ’ s, NL, A1B 3X9, Canada. M.Daniele Fallin, Affiliation/s: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. A.Gulhan Ercan-Sencicek, Affiliation/s: Programs on Neurogenetics, Yale Uni- versity School of Medicine, New Haven, CT 06520, USA. Sean Ennis, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Frederico Duque, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Eftichia Duketis, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Richard Delorme, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, 75015, France, Centre National de la Recherche Scientifique URA 2182 Institut Pasteur, Paris, 75724, France, Department of Child and Adolescent Psychiatry, Robert Debré Hospital, Assistance Publique – Hôpitaux de Paris, Paris, 75019, France, Silvia DeRubeis, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Maretha V DeJonge, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Geraldine Dawson, Affiliation/s: Duke Center for Autism and Brain Developments, Duke University School of Medicine, Durham, NC 27705, USA, Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, NC 27708, USA. Michael L Cuccaro, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Catarina T Correia, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Judith Conroy, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Temple Street Children ’ s University Hospital, Dublin, D1, Ireland. Ines C Conceição, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Andreas G Chiocchetti, Affiliation/s: Depar tment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goe the University Frankfurt, Frankfurt am Main, 60528, Germany. Patrícia BS Celestino-Soper, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indian- apolis, IN 46202, USA. Jillian Casey, Affiliation/s: Temple Street Children ’ s University Hospital, Dublin, D1, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Rita M Cantor, Affiliation/s: Department of Psychiatry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA. Cátia Café, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Jonas Bybjerg-Grauholm, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Sean Brennan, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Thomas Bourgeron, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, University Paris Diderot, Sorbonne Paris Cité, Paris, 75013, France, Patrick F Bolton, Affiliation/s: Institute of Psychiatry, Kings College London, London, SE5 8AF, UK, South London and Maudsley Biomedical Research Centre for Mental Health, London, SE5 8AF, UK. Sven Bölte, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany, Department of Women ’ s and Children ’ s Health, Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, SE- 113 30, Sweden, Child and Adolescent Psychiatry, Center for Psychiatry Re- search, Stockholm County Council, Stockholm, SE-171 77, Sweden. Nadia Bolshakova, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Catalina Betancur, Affiliation/s: INSERM U1130, Paris, 75005, France, CNRS UMR 8246, Paris, 75005, France, Sorbonne Universités, UPMC Univ Paris 6, Neuroscience Paris Seine, Paris, 75005, France. Raphael Bernier, Affiliation/s: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. Arthur L Beaudet, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Agatino Battaglia, Affiliation/s: Stella Maris Institute for Child and Adolescent Neuropsychiatr, Pisa, 56018, Italy. Vanessa H Bal, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Gillian Baird, Affiliation/s: Paediatric Neurodisability, King ’ s Health Partners, Kings College London, London, SE1 7EH, UK. Anthony J Bailey, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK, Mental Health and Addictions Research Unit, University of British Colombia, Vancouver, BC, V5Z 4H4, Canada. Marie Bækvad-Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Joel S Bader, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Elena Bacchelli, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Evdokia Anagnostou, Affiliation/s: Bloorview Research Institute, University of Toronto, Toronto, ON, M4G 1R8, Canada. David Amaral, Affiliation/s: The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Psychiatry, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Behavioural Sciences, School of Medicine, University of California Davis, Davis, CA 95817, USA. Joana Almeida, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Anders D Børglum, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Joseph D Buxbaum, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Aravinda Chakravarti, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Edwin H Cook, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Hilary Coon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Daniel H Geschwind, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Michael Gill, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Hakon Hakonarson, Affiliation/s: The Center for Applied Genomics and Division of Human Genetics, Children ’ s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Dept of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA. Joachim Hallmayer, Affiliation/s: Department of Psychiatry, Stanford University, Stanford, CA 94305, USA. Aarno Palotie, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK., Anney, Richard J. L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertu, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thoma, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A. S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogã©, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnstrã¶m, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, Mcmahon, William M., Mcgrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceiã§ã£o, Ines C., Chiocchetti, Andreas G., Celestino-Soper, PatrÃcia B. S., Casey, Jillian, Cantor, Rita M., Cafã©, Cã¡tia, Bybjerg-Grauholm, Jona, Brennan, Sean, Bourgeron, Thoma, Bolton, Patrick F., Bã¶lte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Bã¸rglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, Daly, Mark J., Hakonarson, Hakon, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Male ,INTELLECTUAL DISABILITY ,Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium ,Autism ,Neurodevelopment ,Gene Expression ,Genome-wide association study ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,lcsh:RC346-429 ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Pair 10 ,Copy-number variation ,Aetiology ,Autism spectrum disorder ,Genetics ,Adaptor Proteins ,Forkhead Transcription Factors ,Serious Mental Illness ,3. Good health ,Mental Health ,Psychiatry and Mental Health ,Meta-analysis ,Female ,Biotechnology ,Human ,Autismo ,Genetic correlation ,Intellectual and Developmental Disabilities (IDD) ,Clinical Sciences ,Gene-set analysi ,Genomics ,Locus (genetics) ,FOXP1 ,Biology ,Chromosomes ,Heritability ,03 medical and health sciences ,Plasma Membrane Calcium-Transporting ATPases ,Developmental Neuroscience ,REVEALS ,mental disorders ,LINKAGE ,medicine ,Journal Article ,Humans ,Genetic Predisposition to Disease ,Meta-analysi ,GENOME-WIDE ASSOCIATION ,COMMON ,Genotyping ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,COPY NUMBER VARIATION ,Genetic association ,Adaptor Proteins, Signal Transducing ,Homeodomain Proteins ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Chromosomes, Human, Pair 10 ,Research ,Human Genome ,Signal Transducing ,Neurosciences ,Membrane Proteins ,medicine.disease ,RISK LOCI ,R1 ,Brain Disorders ,Repressor Proteins ,030104 developmental biology ,Genetic Loci ,Case-Control Studies ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,Schizophrenia ,Carrier Proteins ,Gene-set analysis ,MENTAL-RETARDATION ,SCAN ,030217 neurology & neurosurgery ,Transcription Factors ,Developmental Biology - Abstract
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium - Collaborators (162): Anney RJL, Ripke S, Anttila V, Grove J, Holmans P, Huang H, Klei L, Lee PH, Medland SE, Neale B, Robinson E, Weiss LA, Zwaigenbaum L, Yu TW, Wittemeyer K, Willsey AJ, Wijsman EM, Werge T, Wassink TH, Waltes R, Walsh CA, Wallace S, Vorstman JAS, Vieland VJ, Vicente AM, vanEngeland H, Tsang K, Thompson AP, Szatmari P, Svantesson O, Steinberg S, Stefansson K, Stefansson H, State MW, Soorya L, Silagadze T, Scherer SW, Schellenberg GD, Sandin S, Sanders SJ, Saemundsen E, Rouleau GA, Rogé B, Roeder K, Roberts W, Reichert J, Reichenberg A, Rehnström K, Regan R, Poustka F, Poultney CS, Piven J, Pinto D, Pericak-Vance MA, Pejovic-Milovancevic M, Pedersen MG, Pedersen CB, Paterson AD, Parr JR, Pagnamenta AT, Oliveira G, Nurnberger JI, Nordentoft M, Murtha MT, Mouga S, Mortensen PB, Mors O, Morrow EM, Moreno-De-Luca D, Monaco AP, Minshew N, Merikangas A, McMahon WM, McGrew SG, Mattheisen M, Martsenkovsky I, Martin DM, Mane SM, Magnusson P, Magalhaes T, Maestrini E, Lowe JK, Lord C, Levitt P, Martin CL, Ledbetter DH, Leboyer M, LeCouteur AS, Ladd-Acosta C, Kolevzon A, Klauck SM, Jacob S, Iliadou B, Hultman CM, Hougaard DM, Hertz-Picciotto I, Hendren R, Hansen CS, Haines JL, Guter SJ, Grice DE, Green JM, Green A, Goldberg AP, Gillberg C, Gilbert J, Gallagher L, Freitag CM, Fombonne E, Folstein SE, Fernandez B, Fallin MD, Ercan-Sencicek AG, Ennis S, Duque F, Duketis E, Delorme R, DeRubeis S, DeJonge MV, Dawson G, Cuccaro ML, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Celestino-Soper PBS, Casey J, Cantor RM, Café C, Bybjerg-Grauholm J, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bolshakova N, Betancur C, Bernier R, Beaudet AL, Battaglia A, Bal VH, Baird G, Bailey AJ, Bækvad-Hansen M, Bader JS, Bacchelli E, Anagnostou E, Amaral D, Almeida J, Børglum AD, Buxbaum JD, Chakravarti A, Cook EH, Coon H, Geschwind DH, Gill M, Hallmayer J, Palotie A, Santangelo S, Sutcliffe JS, Arking DE, Devlin B, Daly MJ. Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA. PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/ Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR)
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- 2017
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20. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
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Christian R. Marshall, Annette Estes, John Wei, Janet A. Buchanan, Jennifer L. Howe, Christina Chrysler, Weili Li, Tara Paton, Fiona Tsoi, Zhuozhi Wang, Brendan J. Frey, Eric Deneault, Edwin H. Cook, William Van Etten, Stephen W. Scherer, Mohammed Uddin, Mayada Elsabbagh, Emily Kirby, Sylvia Lamoureux, Cheryl Cytrynbaum, Bhooma Thiruvahindrapuram, Mathew T. Pletcher, Lonnie Zwaigenbaum, Wilson W L Sung, Angie Fedele, Daniele Merico, Bartha Maria Knoppers, Ryan K. C. Yuen, Marc Woodbury-Smith, Worrawat Engchuan, Vicki Seifer, Isabel M. Smith, Barbara Kellam, Bonnie Mackinnon Modi, Stephanie Koyanagi, Bridget A. Fernandez, James T. Robinson, Karen Ho, Edward J Higginbotham, Joe Whitney, Krissy A.R. Doyle-Thomas, Beth A. Malow, Susan Walker, Jeremy R. Parr, Louise Gallagher, Rob Nicolson, Jonathan Bingham, Thomas Nalpathamkalam, Lia D’Abate, Sanne Jilderda, Matt Bookman, Jessica Brian, Sarah J. Spence, Ann Thompson, Jonathan Leef, Rosanna Weksberg, Jacob A. S. Vorstman, Tal Savion-Lemieux, Anne Marie Tassé, Peter Szatmari, Alana Iaboni, Xudong Liu, Evdokia Anagnostou, Jeffrey R. MacDonald, Ny Hoang, Mehdi Zarrei, Lizhen Xu, Simon N. Twigger, Robert H. Ring, Stephen R. Dager, Melissa T. Carter, Irene Drmic, Michael J. Szego, Wendy Roberts, Lili Senman, Giovanna Pellecchia, Rohan V. Patel, Sergio L. Pereira, Joachim Hallmayer, David Glazer, Lisa J. Strug, Ada J.S. Chan, and Nicole A. Deflaux
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0301 basic medicine ,Candidate gene ,DNA Copy Number Variations ,Autism Spectrum Disorder ,Neuroscience(all) ,Biology ,behavioral disciplines and activities ,Polymorphism, Single Nucleotide ,DNA sequencing ,Article ,03 medical and health sciences ,Genetic variation ,mental disorders ,Databases, Genetic ,medicine ,Journal Article ,Humans ,Genetic Predisposition to Disease ,Copy-number variation ,Gene ,Sequence Deletion ,Whole genome sequencing ,Genetics ,Chromosome Aberrations ,General Neuroscience ,Autism spectrum disorders ,medicine.disease ,Phenotype ,Mutagenesis, Insertional ,030104 developmental biology ,Autism spectrum disorder ,Next-generation sequencing ,Genome-Wide Association Study - Abstract
We are performing whole genome sequencing (WGS) of families with Autism Spectrum Disorder (ASD) to build a resource, named MSSNG, to enable the sub-categorization of phenotypes and underlying genetic factors involved. Here, we report WGS of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible in a cloud platform, and through an internet portal with controlled access. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertion/deletions (indels) or copy number variations (CNVs) per ASD subject. We identified 18 new candidate ASD-risk genes such as MED13 and PHF3, and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (p=6×10−4). In 294/2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried CNV/chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.
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- 2017
21. Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes
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Peter Szatmari, Barbara Kellam, Jennifer L. Howe, Kristiina Tammimies, James S. Sutcliffe, Eric Duku, Christina Chrysler, Mohammed Uddin, Veronica J. Vieland, Stephen W. Scherer, Anath C. Lionel, Andrew D. Paterson, Marc Woodbury-Smith, Kathy Whitten, Bridget A. Fernandez, Bhooma Thiruvahindrapduram, Christian R. Marshall, Susan Walker, Ann Thompson, Ryan K. C. Yuen, Morgan Parlier, Joseph Piven, Irene O’Conner, and Daniele Merico
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Male ,Candidate gene ,Genetic Linkage ,Datasets as Topic ,Penetrance ,NDUFV1 ,Pedigree chart ,Biology ,Gene Duplication ,mental disorders ,Gene duplication ,Intellectual disability ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Copy-number variation ,Genetics (clinical) ,Electron Transport Complex I ,Chromosomes, Human, Pair 11 ,NADH Dehydrogenase ,medicine.disease ,Human genetics ,Pedigree ,Glutathione S-Transferase pi ,Child Development Disorders, Pervasive ,Autism spectrum disorder ,Female ,Databases, Nucleic Acid ,Genome-Wide Association Study - Abstract
Copy number variation has emerged as an important cause of phenotypic variation, particularly in relation to some complex disorders. Autism spectrum disorder (ASD) is one such disorder, in which evidence is emerging for an etiological role for some rare penetrant de novo and rare inherited copy number variants (CNVs). De novo variation, however, does not always explain the familial nature of ASD, leaving a gap in our knowledge concerning the heritable genetic causes of this disorder. Extended pedigrees, in which several members have ASD, provide an opportunity to investigate inherited genetic risk factors. In this current study, we recruited 19 extended ASD pedigrees, and, using the Illumina HumanOmni2.5 BeadChip, conducted genome-wide CNV interrogation. We found no definitive evidence of an etiological role for segregating CNVs in these pedigrees, and no evidence that linkage signals in these pedigrees are explained by segregating CNVs. However, a small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative 'developmental/neuropsychiatric' susceptibility gene(s), GSTP1 and NDUFV1.
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- 2014
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22. Synaptic, transcriptional, and chromatin genes disrupted in autism
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Christine Stevens, Michael E. Zwick, Deepthi Rajagopalan, Mara Parellada, David J. Cutler, Li-San Wang, Norio Ozaki, Jinlu Cai, Lauren A. Weiss, Patricia Jiménez González, Jeffrey C. Barrett, Silvia De Rubeis, Helena Kilpinen, Alexander Kolevzon, Timothy W. Yu, Michael John Owen, Geraldine Dawson, Martin Schulte-Rüther, Jeremy R. Parr, Aarno Palotie, Eftichia Duketis, Lambertus Klei, Irene Lee, Bridget A. Fernandez, Aniko Sabo, Matthew W. State, Sarah Curran, Lucy Crooks, Chad M. Schafer, Avi Ma'ayan, Stephen Sanders, Evan T. Geller, Monica Biscaldi, Stephen W. Scherer, Christopher S. Poultney, Mark J. Daly, Patrick Bolton, Kaija Puura, Maria H. Chahrour, Michael Gill, Li Liu, Louise Gallagher, Ryan K. C. Yuen, Jack A. Kosmicki, Abraham Reichenberg, Christine M. Freitag, Shaun Purcell, Andreas G. Chiocchetti, Peter Szatmari, Sabine M. Klauck, Shih-Chen Fu, Christian R. Marshall, Joseph D. Buxbaum, Tarjinder Singh, Bernie Devlin, Chiao-Feng Lin, A. Ercument Cicek, Karola Rehnström, Pamela Sklar, Otto Valladares, Michael Sachse, Terho Lehtimäki, R. Sean Hill, Arthur P. Goldberg, A. Jeremy Willsey, Jing Lei, Branko Aleksic, Menachem Fromer, Yan Kou, Jessica M. Brownfeld, Annette Voran, Kathryn Roeder, Gerard D. Schellenberg, David Skuse, Thomas Lehner, Hilary Coon, Benjamin M. Neale, Iuliana Ionita-Laza, Kristiina Tammimies, Stephen J. Guter, Christopher A. Walsh, James S. Sutcliffe, Xin-Xin He, Alison L. McInnes, Emily L. Crawford, Nicholas G. Campbell, Angel Carracedo, R. Susan Walker, Edwin H. Cook, Kaitlin E. Samocha, and Christina M. Hultman
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Male ,Transcription, Genetic ,Molecular Sequence Data ,Mutation, Missense ,SYNGAP1 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Transcriptional regulation ,Odds Ratio ,Humans ,Exome ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Gene ,Exome sequencing ,Germ-Line Mutation ,030304 developmental biology ,Regulation of gene expression ,Genetics ,0303 health sciences ,Multidisciplinary ,biology ,Chromatin Assembly and Disassembly ,Chromatin ,Histone ,Child Development Disorders, Pervasive ,Mutation ,Synapses ,biology.protein ,Female ,Nerve Net ,030217 neurology & neurosurgery - Abstract
The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
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- 2014
23. Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders
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Joana Almeida, Christian R. Marshall, Hakon Hakonarson, Bárbara Oliveira, Anthony J. Griswold, Jacob A. S. Vorstman, Bhooma Thiruvahindrapuram, Suma Jacob, Judith Conroy, Alistair T. Pagnamenta, Christelle Cabrol, Jeremy R. Parr, Daniel H. Geschwind, Nancy J. Minshew, Xiao Xu, Richard Anney, Sven Bölte, Zhuozhi Wang, Emily L. Crawford, Elsa Delaby, Margaret A. Pericak-Vance, Joachim Hallmayer, Jonathan L. Haines, Dalila Pinto, Susana Mouga, Alexander Kolevzon, Elena Bacchelli, Frederico Duque, Bernie Devlin, Latha Soorya, Cátia Café, Kirsty Wing, Jennifer K. Lowe, Ana Tryfon, Stephen J. Guter, Geraldine Dawson, Tiago R. Magalhaes, Anthony J. Bailey, Michael Gill, Peter Szatmari, Steven Gallinger, Marion Pilorge, James S. Sutcliffe, Bridget A. Fernandez, Herman van Engeland, Catalina Betancur, Guiomar Oliveira, Andrew Green, Eftichia Duketis, Bernadette Rogé, Ann Le Couteur, Evdokia Anagnostou, Michelle Cotterchio, Daniele Merico, Giovanna Pellecchia, Jonathan Green, Regina Regan, Jillian P. Casey, Guiqing Cai, Gerard D. Schellenberg, Jennifer L. Howe, Elena Maestrini, Andrew D. Paterson, L. Alison McInnes, Patrick Bolton, Edwin H. Cook, Richard Delorme, Lambertus Klei, Thomas Bourgeron, Gillian Baird, Christine M. Freitag, Beth A. Dombroski, Andreas G. Chiocchetti, Sabine M. Klauck, Susan E. Folstein, Mafalda Barbosa, Anthony P. Monaco, Marion Leboyer, Nadia Bolshakova, Fritz Poustka, Richard Holt, Kerstin Wittemeyer, Wendy Roberts, Lonnie Zwaigenbaum, Louise Gallagher, Susan G. McGrew, Joseph D. Buxbaum, Graham Casey, Simon Wallace, Catherine Lord, Sean Brennan, Robert Ziman, Alison K. Merikangas, John I. Nurnberger, Christopher Gillberg, Ellen M. Wijsman, Astrid M. Vicente, Inȇs C. Conceição, Sean Ennis, Patricia Jiménez González, Hilary Coon, Raphael Bernier, John R. Gilbert, Ann P. Thompson, Susanne Thomson, Agatino Battaglia, Maretha de Jonge, Michael L. Cuccaro, Catarina Correia, Veronica J. Vieland, Stephen W. Scherer, Pauline Chaste, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Friedman Brain Institute, The Mindich Child Health and Development Institute, The Icahn Institute for Genomics and Multiscale Biology, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Trinity College Dublin-St. James's Hospital, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), McLaughlin Centre, University of Toronto, BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Department of Pathology, Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Prevention & Cancer Control, Cancer Care Ontario, Department of Preventive Medicine, University of Southern California (USC), Department of Pediatrics, University of Alberta, School of Education, University of Birmingham [Birmingham], University of Oxford [Oxford]-Warneford Hospital, Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Institute for Biomedical Imaging and Life Science, University of Coimbra [Portugal] (UC), Vanderbilt University [Nashville], Center for Autism and the Developing Brain (CADB), Weill Medical College of Cornell University [New York], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Health and Society, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), Child Developmental and Behavioral Unit, Hospital Nacional de Niños Dr Sáenz Herrera, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Manchester Academic Health Sciences Centre, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Institute of Child Health, University College of London [London] (UCL), Memorial University of Newfoundland [St. John's], Disciplines of Genetics and Medicine, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Institute of Psychiatry, King‘s College London, Institute of psychiatry, University of Washington [Seattle], Paediatric Neurodisability, King‘s College London-King's Health Partners, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, University of British Columbia (UBC), Bloorview Research Institute, Division of Medical Genetics [Seattle], Departments of Biostatistics and Medicine, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Institute of Neuroscience [Newcastle] (ION), Institutes of Neuroscience and Health and Society, Indiana University School of Medicine, Indiana University System-Indiana University System, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Utah Autism Research Program, University of Utah Psychiatry Department, University of Miami School of Medicine, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Institute for Juvenile Research, University of Illinois [Chicago] (UIC), Department of Neuroscience, Main funders of the Autism Genome Project: Autism Speaks (USA), the Health Research Board (Ireland, AUT/2006/1, AUT/2006/2, PD/2006/48), the Medical Research Council (UK), the Hilibrand Foundation (USA), Genome Canada, the Ontario Genomics Institute, and the Canadian Institutes of Health Research (CIHR), Autism Genome Project Consortium, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), University of Pennsylvania, University of Oxford-Warneford Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Betancur, Catalina, Instituto Nacional de Saude Dr Ricardo Jorge, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Università di Bologna [Bologna] (UNIBO), Mount Sinai Hospital (MSH), University of Toronto-The Hospital for Sick Children, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Gillberg Neuropsychiatry Centre, University of Gothenburg (GU), Stanford University Medical School, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Université de Toulouse (UT)-Université de Toulouse (UT), Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, and Scherer SW.
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Male ,INTELLECTUAL DISABILITY ,pathways ,Genome-wide association study ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Bioinformatics ,DUPLICATIONS ,Intellectual disability ,Gene Regulatory Networks ,Genetics(clinical) ,Copy-number variation ,10. No inequality ,Child ,GDI1 ,Genetics (clinical) ,Sequence Deletion ,COPY NUMBER VARIANTS ,Genetics ,gene networks ,Copy Number Variation ,3. Good health ,Pedigree ,Fragile X syndrome ,Multigene Family ,Female ,Metabolic Networks and Pathways ,de novo ,DNA Copy Number Variations ,autism ,Biology ,rare CNV ,PHENOTYPE ONTOLOGY ,Article ,Structural variation ,mental disorders ,medicine ,Humans ,ddc:610 ,FRAGILE-X-SYNDROME ,GENOME-WIDE ASSOCIATION ,Gene ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,HDAC4 ,SETD5 ,medicine.disease ,CHD2 ,inherited ,STRUCTURAL VARIATION ,DELETIONS ,DE-NOVO MUTATIONS ,Child Development Disorders, Pervasive ,Autism - Abstract
International audience; Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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- 2014
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24. Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion
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Kimberly A. Aldinger, Virginia Kimonis, Denise Horn, Brian H.Y. Chung, Kathleen J. Millen, Rosanna Weksberg, Eva Klopocki, Jillene Kogan, William B. Dobyns, Bridget A. Fernandez, A. James Barkovich, and Annick Toutain
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Cerebellum ,Adolescent ,Genotype ,Chromosomes, Human, Pair 22 ,Developmental Disabilities ,Mutant ,Chromosome Disorders ,Nerve Tissue Proteins ,Single-nucleotide polymorphism ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Article ,Image Processing, Computer-Assisted ,Genetics ,medicine ,Humans ,Autistic Disorder ,Child ,Genetic Association Studies ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Adaptor Proteins, Signal Transducing ,Oligonucleotide Array Sequence Analysis ,Mutation ,Chromosome Mapping ,Infant ,Chromosome ,medicine.disease ,Phenotype ,medicine.anatomical_structure ,Genetic Loci ,Child, Preschool ,Autism ,Chromosome Deletion - Abstract
The 22q13.3 deletion causes a neurodevelopmental syndrome, also known as Phelan-McDermid syndrome (MIM #606232), characterized by developmental delay and severe delay or absence of expressive speech. Two patients with hemizygous chromosome 22q13.3 telomeric deletion were referred to us when brain-imaging studies revealed cerebellar vermis hypoplasia (CBVH). To determine whether developmental abnormalities of the cerebellum are a consistent feature of the 22q13.3 deletion syndrome, we examined brain-imaging studies for 10 unrelated subjects with 22q13 terminal deletion. In seven cases where the availability of DNA and array technology allowed, we mapped deletion boundaries using comparative intensity analysis with single nucleotide polymorphism (SNP) microarrays. Approximate deletion boundaries for three additional cases were derived from clinical or published molecular data. We also examined brain-imaging studies for a patient with an intragenic SHANK3 mutation. We report the first brain-imaging data showing that some patients with 22q13 deletions have severe posterior CBVH, and one individual with a SHANK3 mutation has a normal cerebellum. This genotype-phenotype study suggests that the 22q13 deletion phenotype includes abnormal posterior fossa structures that are unlikely to be attributed to SHANK3 disruption. Other genes in the region, including PLXNB2 and MAPK8IP2, display brain expression patterns and mouse mutant phenotypes critical for proper cerebellar development. Future studies of these genes may elucidate their relationship to 22q13.3 deletion phenotypes.
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- 2012
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25. A Discovery Resource of Rare Copy Number Variations in Individuals with Autism Spectrum Disorder
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Christian R. Marshall, Aparna Prasad, Daisuke Sato, Peggy S. Eis, John Wei, Jessica Rickaby, Chao Lu, Peter Szatmari, Wendy Roberts, Stephen W. Scherer, Eli Hatchwell, Bhooma Thiruvahindrapuram, Bridget A. Fernandez, Anath C. Lionel, and Daniele Merico
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gene copy number ,Male ,Candidate gene ,congenital, hereditary, and neonatal diseases and abnormalities ,genetic structures ,DNA Copy Number Variations ,Genotype ,Population ,Biology ,Investigations ,behavioral disciplines and activities ,Polymorphism, Single Nucleotide ,cytogenetics ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Genetics ,SNP ,Humans ,Copy-number variation ,education ,Child ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Comparative Genomic Hybridization ,Genome, Human ,rare variants ,chromosomal abnormalities ,Phenotype ,Child Development Disorders, Pervasive ,Genetic Loci ,DPYD ,Female ,DNA microarray ,molecular pathways ,030217 neurology & neurosurgery ,SNP array ,Comparative genomic hybridization - Abstract
The identification of rare inherited and de novo copy number variations (CNVs) in human subjects has proven a productive approach to highlight risk genes for autism spectrum disorder (ASD). A variety of microarrays are available to detect CNVs, including single-nucleotide polymorphism (SNP) arrays and comparative genomic hybridization (CGH) arrays. Here, we examine a cohort of 696 unrelated ASD cases using a high-resolution one-million feature CGH microarray, the majority of which were previously genotyped with SNP arrays. Our objective was to discover new CNVs in ASD cases that were not detected by SNP microarray analysis and to delineate novel ASD risk loci via combined analysis of CGH and SNP array data sets on the ASD cohort and CGH data on an additional 1000 control samples. Of the 615 ASD cases analyzed on both SNP and CGH arrays, we found that 13,572 of 21,346 (64%) of the CNVs were exclusively detected by the CGH array. Several of the CGH-specific CNVs are rare in population frequency and impact previously reported ASD genes (e.g., NRXN1, GRM8, DPYD), as well as novel ASD candidate genes (e.g., CIB2, DAPP1, SAE1), and all were inherited except for a de novo CNV in the GPHN gene. A functional enrichment test of gene-sets in ASD cases over controls revealed nucleotide metabolism as a potential novel pathway involved in ASD, which includes several candidate genes for follow-up (e.g., DPYD, UPB1, UPP1, TYMP). Finally, this extensively phenotyped and genotyped ASD clinical cohort serves as an invaluable resource for the next step of genome sequencing for complete genetic variation detection.
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- 2012
26. Rare Deletions at the Neurexin 3 Locus in Autism Spectrum Disorder
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Anath C. Lionel, Andrea K. Vaags, David A. Collier, Bridget A. Fernandez, Susan Walker, Dalila Pinto, Jennelle C. Hodge, Christina Chrysler, Irene Drmic, Daisuke Sato, Wendy Roberts, Eric Fombonne, Patrick Bolton, Peter Szatmari, Christian R. Marshall, Stephen W. Scherer, Caroline Mackie Ogilvie, Carolyn Russell, Dimitri J. Stavropoulos, McKinsey L. Goodenberger, Sarah Curran, Lili Senman, Lonnie Zwaigenbaum, Aparna Prasad, Joo Wook Ahn, Quinn Stein, and Ann Thompson
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Adult ,Male ,Adolescent ,DNA Copy Number Variations ,Neurexin ,Nerve Tissue Proteins ,Penetrance ,Locus (genetics) ,Biology ,Young Adult ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Report ,mental disorders ,medicine ,Genetics ,Humans ,Gene family ,Genetics(clinical) ,Child ,Genetics (clinical) ,030304 developmental biology ,Chromosomes, Human, Pair 14 ,0303 health sciences ,Point mutation ,medicine.disease ,Pedigree ,Child Development Disorders, Pervasive ,Genetic Loci ,Autism spectrum disorder ,Child, Preschool ,Autism ,Female ,Gene Deletion ,030217 neurology & neurosurgery - Abstract
The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3–31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.
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- 2012
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27. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders
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Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Heterozygote ,Adolescent ,[SDV]Life Sciences [q-bio] ,Developmental Disabilities ,Biology ,Body Mass Index ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Gene Order ,Genetics ,medicine ,Humans ,Copy-number variation ,Clinical genetics ,Obesity ,Young adult ,Child ,Genetics (clinical) ,030304 developmental biology ,Child Development Disorders, Pervasive/diagnosis ,Child Development Disorders, Pervasive/genetics ,Chromosome Deletion ,Chromosomes, Human, Pair 16 ,Developmental Disabilities/diagnosis ,Developmental Disabilities/genetics ,Female ,Intelligence Tests ,Phenotype ,Syndrome ,2. Zero hunger ,Psychiatry ,0303 health sciences ,Intelligence quotient ,Neuropsychology ,Complex traits ,medicine.disease ,Comorbidity ,3. Good health ,Autism spectrum disorder ,Child Development Disorders, Pervasive ,Autism ,Medical genetics ,Human medicine ,Copy-Number Variation ,030217 neurology & neurosurgery - Abstract
Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.
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- 2012
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28. Using next-generation sequencing for the diagnosis of rare disorders: a family with retinitis pigmentosa and skeletal abnormalities
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Kasmintan A. Schrader, Steven J.M. Jones, Marco A. Marra, Torsten O. Nielsen, Niki Boyd, Alireza Heravi-Moussavi, Barry Gallagher, Janine Senz, Bridget A. Fernandez, Gavin Ha, David G. Huntsman, Sohrab P. Shah, Terry-Lynn Young, James Whelan, Jane Green, Arusha Oloumi, Patrice Eydoux, Paula J. Waters, and Martin Hirst
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Genetics ,Candidate gene ,Mucolipidosis ,Retinitis pigmentosa ,medicine ,Biology ,medicine.disease ,GNPTG ,Exome ,Genome ,Exome sequencing ,DNA sequencing ,Pathology and Forensic Medicine - Abstract
Linkage analysis with subsequent candidate gene sequencing is typically used to diagnose novel inherited syndromes. It is now possible to expedite diagnosis through the sequencing of all coding regions of the genome (the exome) or full genomes. We sequenced the exomes of four members of a family presenting with spondylo-epiphyseal dysplasia and retinitis pigmentosa and identified a six-base-pair (6-bp) deletion in GNPTG, the gene implicated in mucolipidosis type IIIγ. The diagnosis was confirmed by biochemical studies and both broadens the mucolipidosis type III phenotype and demonstrates the clinical utility of next-generation sequencing to diagnose rare genetic diseases.
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- 2011
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29. A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly
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Terry-Lynn Young, Patrick S. Parfrey, Gordon J. Johnson, Jane Green, Lance P. Doucette, and Bridget A. Fernandez
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Adult ,Male ,Candidate gene ,Newfoundland and Labrador ,Haploinsufficiency ,Biology ,medicine.disease_cause ,Cataract ,Article ,Young Adult ,Dysgenesis ,Corneal Opacity ,Anterior Eye Segment ,Lens, Crystalline ,Genetics ,medicine ,Humans ,Point Mutation ,Eye Abnormalities ,Allele ,Child ,Alleles ,Genetics (clinical) ,Aged ,Mutation ,Point mutation ,Autosomal dominant trait ,Forkhead Transcription Factors ,Sequence Analysis, DNA ,Middle Aged ,Stop codon ,Phenotype ,Female ,Follow-Up Studies - Abstract
Anterior segment dysgenesis (ASD) is a spectrum of disorders that affect the anterior ocular chamber. Clinical studies on a Newfoundland family over the past 30 years show that 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly, segregating as an autosomal dominant trait. To determine the molecular etiology of the variable ASD in this family, we sequenced nine functional candidate genes and identified 44 variants. A point mutation in FOXE3, which codes for a transcription factor involved in the formation of the lens and surrounding structures, co-segregated with the variable ocular phenotype. This novel mutation (c.959G>T) substitutes the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Two recent reports have also identified non-stop mutations in FOXE3 in patients with variable ocular phenotypes and predict an extended protein. Although FOXE3 is a lens-specific gene, we successfully isolated complementary DNA from lymphoblasts of an affected family member, and our sequencing results show that the c.959T allele is absent, suggesting that it may be degraded at the RNA level. Though preliminary, our results challenge the notion that an extended FOXE3 protein causes ASD, and instead suggests a mechanism of haploinsufficiency in the case of non-stop mutations. This study adds to several reports that suggest that autosomal-dominant mutations within FOXE3 cause ASD and has important clinical utility, especially for the diagnosis of mildly affected patients.
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- 2010
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30. Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome
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Bridget A. Fernandez, Birgit Sikkema-Raddatz, Marjolein H. Willemsen, Carlos A. Bacino, Stephen W. Scherer, Arjan P.M. de Brouwer, Erica H. Gerkes, Tjitske Kleefstra, Lorraine Potocki, Christian R. Marshall, Rolph Pfundt, and Hans van Bokhoven
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Male ,Letter ,Genetics and epigenetic pathways of disease [NCMLS 6] ,CHARGE syndrome ,COMPARATIVE GENOMIC HYBRIDIZATION ,Copy-number variation ,Child ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,Genetics ,REARRANGEMENTS ,Nucleic Acid Hybridization ,Zinc Fingers ,Syndrome ,Effective primary care and public health [NCEBP 7] ,Microdeletion syndrome ,Phenotype ,Autism spectrum disorder ,Child, Preschool ,CHARGE-SYNDROME ,Chromosome Deletion ,Haploinsufficiency ,Functional Neurogenomics [DCN 2] ,Adult ,16q24.3 microdeletion ,autism ,Biology ,Mental health [NCEBP 9] ,ANKRD11 ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Young Adult ,medicine ,Humans ,ZNF778 ,RUBINSTEIN-TAYBI-SYNDROME ,Abnormalities, Multiple ,Autistic Disorder ,cognitive impairment ,Rubinstein–Taybi syndrome ,MUTATIONS ,DELETION ,LINKED MENTAL-RETARDATION ,medicine.disease ,DUPLICATION ,Repressor Proteins ,Developmental disorder ,STRUCTURAL VARIATION ,COPY NUMBER ,Autism ,Cognition Disorders ,Chromosomes, Human, Pair 16 - Abstract
The clinical use of array comparative genomic hybridization in the evaluation of patients with multiple congenital anomalies and/or mental retardation has recently led to the discovery of a number of novel microdeletion and microduplication syndromes. We present four male patients with overlapping molecularly defined de novo microdeletions of 16q24.3. The clinical features observed in these patients include facial dysmorphisms comprising prominent forehead, large ears, smooth philtrum, pointed chin and wide mouth, variable cognitive impairment, autism spectrum disorder, structural anomalies of the brain, seizures and neonatal thrombocytopenia. Although deletions vary in size, the common region of overlap is only 90 kb and comprises two known genes, Ankyrin Repeat Domain 11 (ANKRD11) (MIM 611192) and Zinc Finger 778 (ZNF778), and is located approximately 10 kb distally to Cadherin 15 (CDH15) (MIM 114019). This region is not found as a copy number variation in controls. We propose that these patients represent a novel and distinctive microdeletion syndrome, characterized by autism spectrum disorder, variable cognitive impairment, facial dysmorphisms and brain abnormalities. We suggest that haploinsufficiency of ANKRD11 and/or ZNF778 contribute to this phenotype and speculate that further investigation of non-deletion patients who have features suggestive of this 16q24.3 microdeletion syndrome might uncover other mutations in one or both of these genes. European Journal of Human Genetics (2010) 18, 429-435; doi:10.1038/ejhg.2009.192; published online 18 November 2009
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- 2010
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31. Contribution of SHANK3 Mutations to Autism Spectrum Disorder
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Wendy Roberts, Stephen W. Scherer, Dalila Pinto, James S. Sutcliffe, Christian R. Marshall, Peter Szatmari, Rainald Moessner, John B. Vincent, Bridget A. Fernandez, Jennifer Skaug, and Lonnie Zwaigenbaum
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Male ,Chromosomes, Human, Pair 22 ,Chromosomes, Human, Pair 20 ,22q13 deletion syndrome ,Epigenetics of autism ,Nerve Tissue Proteins ,Biology ,medicine.disease_cause ,behavioral disciplines and activities ,Translocation, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Report ,mental disorders ,medicine ,Genetics ,Humans ,Heritability of autism ,Genetics(clinical) ,Autistic Disorder ,Genetics (clinical) ,030304 developmental biology ,Sequence Deletion ,Chromosomes, Human, Pair 14 ,0303 health sciences ,Mutation ,Chromosome Mapping ,Genetic Variation ,DNA ,medicine.disease ,Pedigree ,Developmental disorder ,Autism spectrum disorder ,Autism ,Female ,Haploinsufficiency ,Carrier Proteins ,030217 neurology & neurosurgery - Abstract
Mutations in SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of SHANK3 to the pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.
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- 2007
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32. Reduction in Neural-Tube Defects after Folic Acid Fortification in Canada
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Theophile Niyonsenga, M. I. Van Allen, P. De Wals, Soo Hong Uh, Pamela Zimmer, Nora Lee, R.B. Lowry, M.C. Van den Hof, Fassiatou Tairou, Bridget A. Fernandez, John Evans, Barbara Sibbald, and Marian Crowley
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Vitamin ,Canada ,medicine.medical_specialty ,Fortification ,Encephalocele ,Reduction (complexity) ,chemistry.chemical_compound ,Folic Acid ,Animal science ,Anencephaly ,Prevalence ,medicine ,Humans ,Neural Tube Defects ,Food science ,Neural tube defect ,Spina bifida ,business.industry ,Food fortification ,Infant, Newborn ,Neural tube ,General Medicine ,medicine.disease ,Confidence interval ,Surgery ,Folic acid fortification ,medicine.anatomical_structure ,chemistry ,Food, Fortified ,Vitamin B Complex ,business - Abstract
In 1998, folic acid fortification of a large variety of cereal products became mandatory in Canada, a country where the prevalence of neural-tube defects was historically higher in the eastern provinces than in the western provinces. We assessed changes in the prevalence of neural-tube defects in Canada before and after food fortification with folic acid was implemented.The study population included live births, stillbirths, and terminations of pregnancies because of fetal anomalies among women residing in seven Canadian provinces from 1993 to 2002. On the basis of published results of testing of red-cell folate levels, the study period was divided into prefortification, partial-fortification, and full-fortification periods. We evaluated the relationship between baseline rates of neural-tube defects in each province and the magnitude of the decrease after fortification was implemented.A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each province, and geographical differences almost disappeared after fortification began. The observed reduction in rate was greater for spina bifida (a decrease of 53%) than for anencephaly and encephalocele (decreases of 38% and 31%, respectively).Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.
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- 2007
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33. Male-to-female sex reversal associated with an ∼250 kb deletion upstream of NR0B1 (DAX1)
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Jonathan S. Berg, Pawel Stankiewicz, Marta Smyk, Bridget A. Fernandez, Amber Pursley, Fiona K. Curtis, James R. Lupski, Sau Wai Cheung, and Gabriel A. Bien-Willner
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Genetics ,endocrine system ,medicine.medical_specialty ,Gonadal dysgenesis ,Biology ,Sex reversal ,medicine.disease ,Testis determining factor ,Endocrinology ,Internal medicine ,Congenital adrenal hypoplasia ,Gene duplication ,Adrenal insufficiency ,medicine ,Disorders of sex development ,DAX1 ,Genetics (clinical) - Abstract
Deletion of the dosage sensitive gene NR0B1 encoding DAX1 on chromosome Xp21.2 results in congenital adrenal hypoplasia (AHC), whereas NR0B1 duplication in 46,XY individuals leads to gonadal dysgenesis and a female phenotype. We describe a 21-year-old 46,XY female manifesting primary amenorrhea, a small immature uterus, gonadal dysgenesis, and notably absent adrenal insufficiency with a submicroscopic (257 kb) deletion upstream of NR0B1. We hypothesize that loss of regulatory sequences may have resulted in position effect up-regulation of DAX1 expression, consistent with phenotypic consequences of NR0B1 duplication. We propose that this genomic region and by extension those surrounding the dosage sensitive SRY, SOX9, SF1, and WNT-4 genes, should be examined for copy-number variation in patients with sex reversal.
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- 2007
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34. Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations
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Fowzan S. Alkuraya, Wenjuan Zhang, Daniel H. Cohn, Brian H.Y. Chung, William B. Dobyns, Nancy J. Mendelsohn, Kimberly A. Aldinger, Bridget A. Fernandez, and Cynthia J. Curry
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0301 basic medicine ,Male ,medicine.medical_specialty ,Cerebellum ,Pathology ,Neurology ,Developmental Disabilities ,Wnt1 Protein ,Compound heterozygosity ,Article ,03 medical and health sciences ,Genetics ,Medicine ,Humans ,Genetic Predisposition to Disease ,Cerebellar hypoplasia ,Genetics (clinical) ,Chiari malformation ,business.industry ,Brain ,Human brain ,Anatomy ,Osteogenesis Imperfecta ,medicine.disease ,Phenotype ,Magnetic Resonance Imaging ,030104 developmental biology ,medicine.anatomical_structure ,Osteogenesis imperfecta ,Mutation ,Female ,Nervous System Diseases ,business ,Brain Stem - Abstract
Autosomal recessively inherited mutations in WNT1 were recently identified as a cause of severe osteogenesis imperfecta (OI).1–6 This finding does not address the critical role of Wnt1 in mid-hindbrain development that is well described in model organisms.7 ,8 Severe intellectual and motor deficits were noted in 4 of 16 families reported to date, but few details were provided. We reviewed developmental outcomes and brain-imaging studies for one new and five previously reported individuals with WNT1-associated OI. All six have brain malformations, with prominent brainstem and cerebellar hypoplasia in five of these six individuals. Homozygous or compound heterozygous mutations in WNT1 were recently described as a novel cause for severe autosomal-recessive OI in 25 individuals from 16 families in a series of six papers.1–6 Brain-imaging studies in two individuals were reported to show unilateral cerebellar hypoplasia,2 ,4 and another was reported to have Chiari malformation type 1.5 However, only limited data were presented regarding the brain and neurological phenotypes, including only a single MRI image. This is an important issue to address, as the WNT family of secreted signalling proteins play key roles in many developmental and homeostatic processes.9 Indeed, prominent defects in early brain development were described in two mouse lines with Wnt1 mutations long before WNT1 mutations were identified as a cause of bone fragility in humans.7 ,8 To examine the human brain phenotype associated with mutations in WNT1 , we reviewed all available brain-imaging studies from one new and five previously reported individuals including one sibling pair,1–5 which consisted of five brain MRI (figure 1) and one cranial CT scan (see online supplementary figure S1). We found significant malformations in all six individuals (table 1). Hippocampal malformations were found in three affected individuals for whom coronal MRI …
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- 2015
35. Primary Adrenocortical Insufficiency Case Series: Genetic Etiologies More Common than Expected
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Fiona Curtis, Bridget A. Fernandez, Joseph Curtis, Lou Metherell, Sarah L. Tsai, Jane Green, and Ara Healey
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0301 basic medicine ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Lipoid congenital adrenal hyperplasia ,030209 endocrinology & metabolism ,Primary Adrenal Insufficiency ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Addison Disease ,medicine ,Adrenal insufficiency ,Humans ,Primary adrenocortical insufficiency ,Child ,business.industry ,Homozygote ,medicine.disease ,Phosphoproteins ,030104 developmental biology ,Addison's disease ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Immunology ,Mutation ,Etiology ,Female ,Presentation (obstetrics) ,business ,Receptor, Melanocortin, Type 2 ,Transcription Factors - Abstract
Background/Aims: Primary adrenal insufficiency (AI) is an important cause of morbidity in children. Our objectives were: (1) to describe the clinical presentation of children with new-onset primary AI, and (2) to identify monogenic causes of primary AI in children. Methods: Chart review and mutation detection in candidate genes were conducted for 11 patients with primary AI. Results: The likely cause of AI was determined in 9 patients. One had a homozygous MC2R mutation associated with familial glucocorticoid deficiency. Two had the same homozygous mutation in the AIRE gene which is associated with type 1 autoimmune polyglandular syndrome. One patient had a heterozygous change in this gene of undetermined significance. Five were homozygous for the previously reported p.R188C STAR mutation causing nonclassic lipoid congenital adrenal hyperplasia, representing the largest cohort of such patients from a single geographic area. In the remaining 2 patients, no clear etiology was identified. Conclusions: We recommend genetic testing for patients who have negative anti-adrenal antibodies or suggestive family history. Diagnosing a genetic etiology can provide information about prognosis and treatment, and is therefore beneficial for patients. Our high proportion of patients with nonclassic lipoid congenital adrenal hyperplasia likely represents a founder effect.
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- 2015
36. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond
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George Zogopoulos, Pardeep Kaurah, Sohrab P. Shah, Michelle M.M. Woo, Kasmintan A. Schrader, Janine Senz, Aline Talhouk, Carlos Caldas, G. Keller, Cydney B. Nielsen, Isabel Claro, Amy Lum, Hugo Pinheiro, Katie Baker-Lange, Andrée MacMillan, Carla Oliveira, Hector Li-Chang, Parry Guilford, Samantha Hansford, Sarah Padilla, David F. Schaeffer, Teresa Almeida Santos, Franco Roviello, Erin Pennell, Giovanni Corso, David G. Huntsman, Ivy Lewis, Bridget A. Fernandez, Paul D.P. Pharoah, Steven Gallinger, Noralane M. Lindor, Karey Shumansky, Susan Richardson, Henry T. Lynch, and Joana Carvalho
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Adult ,Male ,Cancer Research ,Canada ,Heredity ,PALB2 ,DNA Mutational Analysis ,STK11 ,Breast Neoplasms ,Penetrance ,Bioinformatics ,medicine.disease_cause ,Risk Assessment ,Young Adult ,Germline mutation ,Breast cancer ,Age Distribution ,Sex Factors ,Antigens, CD ,Predictive Value of Tests ,Risk Factors ,Stomach Neoplasms ,medicine ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Sex Distribution ,Germ-Line Mutation ,Aged ,Aged, 80 and over ,Mutation ,business.industry ,Incidence ,Age Factors ,Cancer ,Middle Aged ,medicine.disease ,Cadherins ,Pedigree ,Europe ,Phenotype ,Oncology ,Female ,Hereditary diffuse gastric cancer ,business - Abstract
Importance E-cadherin ( CDH1 ) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. Objectives To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. Design, Setting, and Participants Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. Main Outcomes and Measures Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. Results Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation–negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1 , BRCA2 , STK11 , SDHB , PRSS1 , ATM , MSR1 , and PALB2 . Conclusions and Relevance This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1 . Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.
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- 2015
37. Bayesian Small Area Cluster Analysis of Neural Tube Defects in Newfoundland
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F.B. Maroun, Bridget A. Fernandez, Marian Crowley, and J. Scott Sloka
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Male ,medicine.medical_specialty ,Time Factors ,Newfoundland and Labrador ,Disease cluster ,Article ,Folic Acid ,Epidemiology ,medicine ,Cluster Analysis ,Humans ,Neural Tube Defects ,Small-Area Analysis ,Neural tube defect ,business.industry ,Incidence ,Incidence (epidemiology) ,Infant, Newborn ,Public Health, Environmental and Occupational Health ,Ecological study ,Bayes Theorem ,General Medicine ,medicine.disease ,Relative risk ,Vitamin B Complex ,Female ,business ,Live birth ,Demography - Abstract
BACKGROUND: The incidence of neural tube defects (NTDs) is declining worldwide due to the implementation of folic acid supplementation programs. Such a program was implemented over 1996–97 in Newfoundland and Labrador, Canada. The geographical distribution of birth incidence was studied prior to and after the implementation of the program to identify regions of residual high incidence. Excess residual cases may potentially be due to genetic causes or incomplete supplementation program implementation. METHODS: Maternal place of residence for all provincial live birth and stillbirth notifications, provincial maternal-fetal medicine referrals, provincial rehabilitation referrals, and all provincial hospitals with NTDs or terminations for NTDs was obtained from 1975 to 2002 for near complete case ascertainment. Bayesian small area analysis was separately performed on cases from 1975–1996 and 1997–2002. The two time periods were compared. RESULTS: Birth incidence of NTDs was noted to decline after 1996, from 5.54/1000 live births to 1.08/1000 live births. 592 cases were found from 1975–1996 and 34 cases from 1997–2002. Relative risk of birth incidence was 0.93–1.18 (95% CI) for 1975–1996 and 0.97–1.02 for 1997–2002 after Bayesian smoothing. One region had an excess of residual cases greater than 34%. CONCLUSIONS: The implications of this observation to the management of the public health initiative imply that overall response to the decrease in cases tends to be uniform across the province, with potentially one area of interest where extra efforts may be devoted.
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- 2006
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38. Holoprosencephaly and cleidocranial dysplasia in a patient due to two position-effect mutations: case report and review of the literature
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Ikuko Teshima, J. Siegel-Bartelt, Bridget A. Fernandez, Stephen W. Scherer, and Jo-Anne Herbrick
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musculoskeletal diseases ,Genetics ,Cleidocranial Dysplasia ,Breakpoint ,Translocation Breakpoint ,Locus (genetics) ,Biology ,medicine.disease ,Osteochondrodysplasia ,Holoprosencephaly ,Skeletal disorder ,medicine ,biology.protein ,Sonic hedgehog ,Genetics (clinical) - Abstract
Holoprosencephaly (HPE) is a genetically heterogeneous developmental field defect in which midline cleavage of the forebrain and craniofacial structures is impaired. Based on the analysis of HPE patients with chromosome rearrangements, at least six loci for the disorder have been assigned. The sonic hedgehog gene (SHH) at 7q36 has been identified as the HPE3 locus. Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by clavicular, pelvic and dental anomalies. It is caused by mutations in the osteoblast-specific transcription factor CBFA1/RUNX2, which maps to 6p21. We report a 20-year-old female with premaxillary agenesis (part of the HPE spectrum), as well as skeletal abnormalities and impacted teeth reminiscent of CCD. She carries a de novo 6;7 reciprocal translocation, with breakpoints at 6p21.1 and 7q36. We have shown previously that the 7q36 breakpoint maps 15 kb telomeric to the 5' end of SHH, which explains the patient's HPE phenotype. Now, using fluorescence in situ hybridization, we have identified a P1 artificial chromosome clone 800 kb upstream of CBFA1/RUNX2 that spans the 6p breakpoint. We propose that the proband's complex phenotype is due to two position-effect (PE) mutations, one at each translocation breakpoint, which have altered the expression of the SHH and CBFA1/RUNX2 genes. The role of PE mutations in human disease is also reviewed.
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- 2005
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39. The Newfoundland population: a unique resource for genetic investigation of complex diseases
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Albert Jones, Joseph Curtis, Lynette Peddle, Sylvia Bartlett, Nelson B. Freimer, Proton Rahman, and Bridget A. Fernandez
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Genetics ,education.field_of_study ,Linkage disequilibrium ,Newfoundland and Labrador ,Population ,Genetic Diseases, Inborn ,Population genetics ,General Medicine ,Biology ,Founder Effect ,Linkage Disequilibrium ,Genetic architecture ,Gene mapping ,Genetic drift ,Humans ,Identification (biology) ,education ,Molecular Biology ,Genetics (clinical) ,Founder effect - Abstract
The population of the province of Newfoundland and Labrador is genetically isolated. This isolation is evidenced by an overabundance of several monogenic disorders. The Newfoundland population, like that of other isolates, is now the focus of interest for identification of genes implicated in common diseases. However, the utility of such populations for this purpose remains unproven. In this paper, we review the current genetic architecture of the province, with respect to geographic isolation, homogeneity, founder effect, genetic drift and extended linkage disequilibrium. Based on these factors, we propose that the population of Newfoundland offers many advantages for genetic mapping of common diseases, compared with admixed populations, and even compared with other isolates.
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- 2003
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40. Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000
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H. Hogg, A Sajoo, D MacGregor, Laura C. Collins, F Robert, H Hare, Cheryl R. Greenberg, A Shugar, Alasdair G. W. Hunter, D Allingham-Hawkins, M. M. Khalifa, T. T. Chiu, S Cardwell, Patrick MacLeod, Stephen P. Sanders, R Lokkesmoe, Wendy S. Meschino, Sandra A. Farrell, J. P. Welch, J Beis, Judith Allanson, Bridget A. Fernandez, Michael R. Hayden, C Riddell, J Schween, E Lemire, S Creighton, Anne Summers, Jennifer MacKenzie, and E. Almqvist
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Genetic counseling ,Prenatal diagnosis ,Retrospective cohort study ,medicine.disease ,Huntington's disease ,Internal medicine ,Genetics ,Medicine ,Age of onset ,Family history ,business ,Predictive testing ,Genetics (clinical) ,Genetic testing - Abstract
Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.
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- 2003
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41. Correspondence
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Brian H.Y. Chung, Chumei Li, Bridget A. Fernandez, and David Chitayat
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Male ,medicine.medical_specialty ,business.industry ,General Medicine ,medicine.disease ,Pathology and Forensic Medicine ,Surgery ,Tongue ,Ulnar–mammary syndrome ,Pediatrics, Perinatology and Child Health ,Humans ,Medicine ,Female ,Anatomy ,Ulnar Neuropathies ,business ,Genetics (clinical) - Published
- 2012
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42. The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position statement of the Canadian College of medical geneticists
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Stacey Hume, Jacques L. Michaud, Kym M. Boycott, Sherry Taylor, Karen Chong, Bekim Sadikovic, Roberto Mendoza-Londono, Julie Lauzon, Christine M. Armour, Julie Richer, Michael T. Geraghty, David Skidmore, Clara D.M. van Karnebeek, Tracy Stockley, Tanya N. Nelson, Jan M. Friedman, Taila Hartley, Ma'n H. Zawati, Jacek Majewski, Bartha Maria Knoppers, Bridget A. Fernandez, Shelin Adam, M. Stephen Meyn, Anne-Marie Laberge, Francois P. Bernier, and Other departments
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medicine.medical_specialty ,Canada ,Best practice ,Genetic counseling ,Genetics, Medical ,Context (language use) ,Translational Research, Biomedical ,Informed consent ,Epidemiology ,Genetics ,Medicine ,Humans ,Canadian Healthcare System ,Position Statement ,Genetics (clinical) ,Genome-Wide Sequencing ,business.industry ,Genetic heterogeneity ,Genome, Human ,Genetic Diseases, Inborn ,Sequence Analysis, DNA ,Return of Results ,3. Good health ,Family medicine ,Medical genetics ,business ,Return of results ,Clinical Guidelines - Abstract
Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally.
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- 2015
43. Molecular Genetic Studies of Human Chromosome 7 in Russell–Silver Syndrome
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Stephen W. Scherer, Theresa A. Grebe, Makiko Meguro, Ikuko Teshima, Kohzoh Mitsuya, Mitsuo Oshimura, Paromita Deb-Rinker, Kazuhiko Nakabayashi, Bridget A. Fernandez, David Chitayat, Jeffrey E. Ming, Jo-Anne Herbrick, Virginia K. Proud, Cynthia J. Curry, Rosanna Weksberg, and Cheryl Shuman
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Molecular Sequence Data ,Chromosomal rearrangement ,Russell-Silver Syndrome ,Hybrid Cells ,Biology ,Mice ,Gene mapping ,Genetics ,medicine ,Animals ,Humans ,Abnormalities, Multiple ,Amino Acid Sequence ,In Situ Hybridization, Fluorescence ,Chromosomal inversion ,Chromosome Aberrations ,Chromosome 7 (human) ,Sequence Homology, Amino Acid ,medicine.diagnostic_test ,Facies ,Sequence Analysis, DNA ,Syndrome ,medicine.disease ,Body Height ,Uniparental disomy ,Cytogenetic Analysis ,Genomic imprinting ,Chromosomes, Human, Pair 7 ,Fluorescence in situ hybridization - Abstract
Russell-Silver syndrome (RSS) is a form of congenital short stature characterized by severe growth retardation and variable dysmorphic features. In some RSS individuals, alterations in imprinted genes may be involved because approximately 7% of sporadic patients have been observed to have maternal uniparental disomy (mUPD) of chromosome 7. RSS patients with structural abnormalities of chromosome 7 have also been described. In these individuals the chromosome rearrangement could disrupt the balance of imprinted genes, contribute to a recessive form of RSS, or lead to haploinsufficiency of a crucial developmental gene product. Because the mechanism and molecular defects on chromosome 7 causing RSS are still unknown, we tested our collection of 77 RSS families for mUPD7 and were able to identify three new cases. We also characterized two RSS patients with de novo cytogenetic abnormalities involving the short arm of chromosome 7. One had a partial duplication [46, XX, dup(7)(p12 p14)] and the second contained a paracentric inversion [46, XY, inv(7)(p14 p21)]. Fluorescence in situ hybridization (FISH) mapping revealed that the breakpoints on 7p14 were localized to the same novel gene, C7orf10, which encompasses >700 kb of DNA. We also identified other transcription units from this immediate region, but all seem to be biallelically expressed when using a somatic cell hybrid assay.
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- 2002
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44. Disruption of the ASTN2 / TRIM32 locus at 9q33.1 is a risk factor in males for Autism Spectrum Disorders, ADHD and other neurodevelopmental phenotypes
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Patricia I. Bader, Christina Chrysler, Pietro Cavalli, Mohammed Uddin, Carlo Poggiani, Noam Soreni, Andrew D. Paterson, Roberto Ciccone, Diana Postorivo, Sebastiano A. Musumeci, Lonnie Zwaigenbaum, Eli Hatchwell, Michael E. Talkowski, Sarah M. Nikkel, Paul D. Arnold, H. Melanie Bedford, Vincenzo Antona, Sylvia Lamoureux, Caroline Mackie Ogilvie, Timothy Wilks, John Wei, Eva M Tomiak, Ugo Cavallari, Marc Woodbury-Smith, Orsetta Zuffardi, Susan Walker, Bob Argiropoulos, Judy Chernos, Charu Deshpande, Jeffrey R. MacDonald, Bai-Lin Wu, Thomas Nalpathamkalam, Lone W. Laulund, Anna Maria Nardone, Gioacchino Scarano, Bridget A. Fernandez, Christian R. Marshall, John Trounce, Susan Leather, Peter Szatmari, Anath C. Lionel, Jennelle C. Hodge, Ann C White, Dimitri J. Stavropoulos, Matteo Della Monica, David S Cobb, Cassandra K. Runke, Zhuozhi Wang, Corrado Romano, Michael T. Geraghty, Leopoldo Zelante, Joo Wook Ahn, Matthew J. Gazzellone, Leonardo Zoccante, Marsha Speevak, Bhooma Thiruvahindrapuram, Russell Schachar, Jennifer L. Howe, Jill Clayton-Smith, Christina Fagerberg, R. Brian Lowry, Francesca Novara, Marco Fichera, Jill A. Rosenfeld, Charlotte Brasch-Andersen, Stephen W. Scherer, Giovanna Pellecchia, Divya Mandyam, Vamsee Pillalamarri, Yu An, Wendy Roberts, Abdul Noor, Daniel Tolson, Melissa T. Carter, Peggy S. Eis, Joyce So, Jennifer Crosbie, Massimo Carella, Ryan K. C. Yuen, Andrea K. Vaags, Mark J Sorensen, Daniele Merico, Kristiina Tammimies, and Yiping Shen
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Male ,Receptors, Cell Surface/genetics ,Autism ,Child Development Disorders, Pervasive/genetics ,Gene Expression ,Genome-wide association study ,Medical and Health Sciences ,Tripartite Motif Proteins ,Risk Factors ,Receptors ,2.1 Biological and endogenous factors ,Protein Isoforms ,Nerve Tissue Proteins/genetics ,Copy-number variation ,Aetiology ,Child ,Genetics (clinical) ,Sequence Deletion ,Pediatric ,Genetics & Heredity ,Genetics ,education.field_of_study ,Single Nucleotide ,Articles ,General Medicine ,Exons ,Biological Sciences ,Mental Health ,Phenotype ,Autism spectrum disorder ,Organ Specificity ,Cerebellar cortex ,Child, Preschool ,Cell Surface ,Speech delay ,Female ,medicine.symptom ,Transcription Initiation Site ,Attention Deficit Disorder with Hyperactivity/genetics ,Chromosomes, Human, Pair 9 ,Human ,Pair 9 ,Adult ,Pediatric Research Initiative ,Child Development Disorders ,Adolescent ,DNA Copy Number Variations ,Intellectual and Developmental Disabilities (IDD) ,Ubiquitin-Protein Ligases ,Population ,Transcription Factors/genetics ,Nerve Tissue Proteins ,Receptors, Cell Surface ,Biology ,Polymorphism, Single Nucleotide ,Chromosomes ,Young Adult ,Clinical Research ,Protein Isoforms/genetics ,Behavioral and Social Science ,medicine ,Attention deficit hyperactivity disorder ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Preschool ,education ,Molecular Biology ,Genetic Association Studies ,Pervasive ,Glycoproteins ,Human Genome ,Neurosciences ,Infant, Newborn ,Glycoproteins/genetics ,Infant ,Newborn ,medicine.disease ,Brain Disorders ,Attention Deficit Disorder with Hyperactivity ,Child Development Disorders, Pervasive ,Case-Control Studies ,Transcription Factors - Abstract
Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
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- 2014
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45. Compound heterozygosity for the achondroplasia-hypochondroplasia FGFR3 mutations: Prenatal diagnosis and postnatal outcome
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David Chitayat, Allen Gardner, Michael Sgro, Phyllis Glance, Peter N. Ray, Lori Moore, Dianne Allingham-Hawkins, Michael Dunn, Kathy Chun, and Bridget A. Fernandez
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musculoskeletal diseases ,medicine.medical_specialty ,Down syndrome ,Pediatrics ,medicine.diagnostic_test ,business.industry ,Hypochondroplasia ,Prenatal diagnosis ,medicine.disease ,Compound heterozygosity ,Osteochondrodysplasia ,Frontal Bossing ,Endocrinology ,Internal medicine ,medicine ,Amniocentesis ,Achondroplasia ,business ,Genetics (clinical) - Abstract
We report on a male newborn infant, a compound carrier of heterozygous mutations in the FGFR3 gene causing achondroplasia and hypochondroplasia. The mother has achondroplasia and carries the common G1138 (G380R) mutation in the FGFR3 gene; the father has hypochondroplasia due to the C1620A (N540K) mutation in the same gene. The fetus was found to carry both mutations diagnosed prenatally by amniocentesis at 17.6 weeks of gestation, following maternal serum screening which showed an increased risk for Down syndrome (1:337). Detailed fetal ultrasound studies showed a large head, short limbs, and a small chest at 22 weeks of gestation. The changes were more severe than those of either achondroplasia or hypochondroplasia. The patient was born by cesarean section at 38 weeks of gestation and had rhizomelic shortness of the upper and lower limbs with excess skin folds, large head, enlarged fontanelles, frontal bossing, lumbar gibbus, trident position of the fingers, and a narrow chest with a horizontal line of demarcation at the narrowest area of the chest. Skeletal radiographs showed shortness of the long bones and flare of metaphyses. He had respiratory difficulties and was treated with nasal prongs. Seizures developed on day 2 of life and recurred on day 9 and responded to treatment with phenobarbital. Brain computed tomographic scan showed possible grey matter heterotopia, partial agenesis of the corpus callosum, and cortical dysplasia. To our knowledge, there are only two previously published cases of compound heterozygous achondroplasia-hypochondroplasia patients. The diagnosis was confirmed by DNA mutation analysis of the FGFR3 gene in both cases.
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- 1999
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46. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy
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Eva M. Reinthaler, Dennis Lal, Sebastien Lebon, Michael S. Hildebrand, Hans-Henrik M. Dahl, Brigid M. Regan, Martha Feucht, Hannelore Steinböck, Birgit Neophytou, Gabriel M. Ronen, Laurian Roche, Ursula Gruber-Sedlmayr, Julia Geldner, Edda Haberlandt, Per Hoffmann, Stefan Herms, Christian Gieger, Melanie Waldenberger, Andre Franke, Michael Wittig, Susanne Schoch, Albert J. Becker, Andreas Hahn, Katrin Männik, Mohammad R. Toliat, Georg Winterer, Holger Lerche, Peter Nürnberg, Heather Mefford, Ingrid E. Scheffer, Samuel F. Berkovic, Jacques S. Beckmann, Thomas Sander, Sebastien Jacquemont, Alexandre Reymond, Fritz Zimprich, Bernd A. Neubauer, Bernd Neubauer, Martina Mörzinger, Arvid Suls, Sarah Weckhuysen, Lieve Claes, Liesbet Deprez, Katrien Smets, Tine Van Dyck, Tine Deconinck, Peter De Jonghe, Rikke S Møller, Laura L. Klitten, Helle Hjalgrim, Kiel Campus, Ingo Helbig, Hiltrud Muhle, Philipp Ostertag, Sarah von Spiczak, Ulrich Stephani, Holger Trucks, Christian E. Elger, Ailing A. Kleefuß-Lie, Wolfram S. Kunz, Rainer Surges, Verena Gaus, Dieter Janz, Bettina Schmitz, Felix Rosenow, Karl Martin Klein, Philipp S. Reif, Wolfgang H. Oertel, Hajo M. Hamer, Felicitas Becker, Yvonne Weber, Bobby P.C. Koeleman, Carolien de Kovel, Dick Lindhout, Agnès Ameil, Joris Andrieux, Sonia Bouquillon, Odile Boute, Jeanne de Flandre, Jean Marie Cuisset, Jean-Christophe Cuvellier, Roger Salengro, Albert David, Bert de Vries, Marie-Ange Delrue, Martine Doco-Fenzy, Bridget A. Fernandez, Delphine Heron, Boris Keren, Robert Lebel, Bruno Leheup, Suzanne Lewis, Maria Antonietta Mencarelli, Cyril Mignot, Jean-Claude Minet, Alexandre Moerman, Fanny Morice-Picard, Mafalda Mucciolo, Katrin Ounap, Laurent Pasquier, Florence Petit, Francesca Ragona, Evica Rajcan-Separovic, Alessandra Renieri, Claudine Rieubland, Damien Sanlaville, Elisabeth Sarrazin, Yiping Shen, Mieke van Haelst, Anneke Vulto-van Silfhout, 16p11.2 European Consortium, EPICURE Consortium, EuroEPINOMICS Consortium, Reinthaler, EM., Zimprich, F., Feucht, M., Steinböck, H., Neophytou, B., Geldner, J., Gruber-Sedlmayr, U., Haberlandt, E., Ronen, GM., Roche, L., Lal, D., Nürnberg, P., Sander, T., Lerche, H., Neubauer, B., Mörzinger, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Møller, RS., Klitten, LL., Hjalgrim, H., Campus, K., Helbig, I., Muhle, H., Ostertag, P., von Spiczak, S., Stephani, U., Trucks, H., Elger, CE., Kleefuß-Lie, AA., Kunz, WS., Surges, R., Gaus, V., Janz, D., Schmitz, B., Rosenow, F., Klein, KM., Reif, PS., Oertel, WH., Hamer, HM., Becker, F., Weber, Y., Koeleman, BP., de Kovel, C., Lindhout, D., Ameil, A., Andrieux, J., Bouquillon, S., Boute, O., Cordier, MP., Cuisset, JM., Cuvellier, JC., David, A., de Vries, B., Delrue, MA., Doco-Fenzy, M., Fernandez, BA., Heron, D., Keren, B., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Mignot, C., Minet, JC., Moerman, A., Morice-Picard, F., Mucciolo, M., Ounap, K., Pasquier, L., Petit, F., Ragona, F., Rajcan-Separovic, E., Renieri, A., Rieubland, C., Sanlaville, D., Sarrazin, E., Shen, Y., van Haelst, M., Vulto-van Silfhout, A., and Other departments
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Male ,DNA Copy Number Variations ,Chromosomes, Human, Pair 22 ,610 Medicine & health ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Temporal lobe ,Epilepsy ,Gene duplication ,Chromosome Duplication ,Genetics ,medicine ,Humans ,Copy-number variation ,Child ,Molecular Biology ,Genetics (clinical) ,Chromosomes, Human, Pair 15 ,Infant ,General Medicine ,Odds ratio ,medicine.disease ,Epilepsy, Rolandic ,Rolandic epilepsy ,Exact test ,Chromosomes, Human, Pair 1 ,Child, Preschool ,Female ,Chromosomes, Human, Pair 16 - Abstract
Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.
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- 2014
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47. A molecular genetic study of autism and related phenotypes in extended pedigrees
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Joseph Piven, Kimberly A. Walters, Peter Szatmari, Yungui Huang, Ann Thompson, Veronica J. Vieland, Bridget A. Fernandez, Mark Woodbury-Smith, Morgan Parlier, and Irene O’Conner
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genetic structures ,Autism ,Cognitive Neuroscience ,Pedigree chart ,behavioral disciplines and activities ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Genetic linkage ,mental disorders ,Genotype ,Genetics ,medicine ,030304 developmental biology ,Linkage (software) ,0303 health sciences ,Linkage ,business.industry ,Research ,Posterior probability of linkage ,medicine.disease ,Phenotype ,Human genetics ,Pedigree ,Autism spectrum disorder ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Background Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD. Methods We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior. Results Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas 'repetitive behavior’, showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study. Conclusions These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD.
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- 2013
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48. Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures
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Bhooma Thiruvahindrapuram, Aparna Prasad, Evdokia Anagnostou, John B. Vincent, Christian R. Marshall, Salman Kirmani, Lyudmila Georgieva, Jennelle C. Hodge, Eric Fombonne, Stephen W. Scherer, Christian Windpassinger, Hong Yang Chen, Matthew J. Gazzellone, Susan Walker, Anath C. Lionel, Anne S. Bassett, Lonnie Zwaigenbaum, Katharina M. Roetzer, Erwin Petek, Peter Szatmari, Linda M. Brzustowicz, Elyse Mitchell, Wendy Roberts, Daniele Merico, George Kirov, Wolfgang Kaschnitz, Bridget A. Fernandez, Gerald Egger, Gregory Costain, Andrea K. Vaags, Rosario R. Trifiletti, and Daisuke Sato
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Male ,Cell Adhesion Molecules, Neuronal ,RNA Splicing ,Synaptic Membranes ,Nerve Tissue Proteins ,medicine.disease_cause ,Epileptogenesis ,Epilepsy ,Exon ,Receptors, Glycine ,Receptors, GABA ,Seizures ,Genetics ,medicine ,Guanine Nucleotide Exchange Factors ,Humans ,Autistic Disorder ,Molecular Biology ,Neural Cell Adhesion Molecules ,Genetics (clinical) ,Sequence Deletion ,Chromosomes, Human, Pair 14 ,Mutation ,Gephyrin ,biology ,Base Sequence ,Calcium-Binding Proteins ,Membrane Proteins ,General Medicine ,Exons ,medicine.disease ,Autism spectrum disorder ,biology.protein ,Schizophrenia ,Autism ,Female ,Carrier Proteins ,Collybistin ,Rho Guanine Nucleotide Exchange Factors - Abstract
The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3–5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.
- Published
- 2013
49. Genome-wide characteristics of de novo mutations in autism
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Jun Wang, Christian R. Marshall, Bhooma Thiruvahindrapuram, Brendan J. Frey, Lonnie Zwaigenbaum, Mohammed Uddin, Ryan K. C. Yuen, Yingrui Li, Wendy Roberts, Dandan Cao, Lia D’Abate, Xiaomin Liu, Xueli Wu, Matt Bookman, Zhuozhi Wang, Ada Js Chan, Michelle T. Siu, Kristiina Tammimies, Ze Zhou, Jonathan Bingham, Hongzhi Cao, David Glazer, Rosanna Weksberg, Yuhui Sun, Susan Walker, Evdokia Anagnostou, Jeffrey R. MacDonald, Daniele Merico, Samuel S Gross, Mehdi Zarrei, Dion Loy, Giovanna Pellecchia, Thomas Nalpathamkalam, Babak Alipanahi, Xun Xu, Xin Jin, Tao Zhang, Mathew T. Pletcher, Xin Tong, Eric Deneault, Stephen W. Scherer, Jian Wang, Peter Szatmari, Robert H. Ring, Mingbang Wang, Huanming Yang, Jennifer L. Howe, and Bridget A. Fernandez
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0301 basic medicine ,Whole genome sequencing ,Genetics ,Mutation rate ,Biology ,medicine.disease ,Genome ,Germline ,Article ,03 medical and health sciences ,030104 developmental biology ,mental disorders ,medicine ,Autism ,Copy-number variation ,Epigenetics ,Molecular Biology ,Gene ,Genetics (clinical) - Abstract
De novo mutations (DNMs) are important in autism spectrum disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole-genome sequencing (WGS) of 200 ASD parent–child trios and characterised germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (P=4.2×10−10). However, when clustered DNMs (those within 20 kb) were found in ASD, not only did they mostly originate from the mother (P=7.7×10−13), but they could also be found adjacent to de novo copy number variations where the mutation rate was significantly elevated (P=2.4×10−24). By comparing with DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (P=8.0×10−9; odds ratio=1.84), of which 15.6% (P=4.3×10−3) and 22.5% (P=7.0×10−5) were non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, regulatory sequences involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD-risk and epigenetic genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the aetiology of ASD.
- Published
- 2016
50. Lethal Disorder of Mitochondrial Fission Caused by Mutations in DNM1L
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Bridget A. Fernandez, Mark E. Samuels, Kyong-Soon Lee, Francois P. Bernier, Stephen W. Scherer, Michael Brudno, Zeenat Malam, Jacques L. Michaud, Kym M. Boycott, Jan M. Friedman, Grace Yoon, Christian R. Marshall, Cynthia Hawkins, Tara Paton, Zhenya Ivakine, Ronald D. Cohn, Bartha Maria Knoppers, and Ella Hyatt
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Dynamins ,Male ,0301 basic medicine ,Heterozygote ,Mitochondrial Diseases ,DNA Mutational Analysis ,Nonsense mutation ,Formins ,Biology ,Compound heterozygosity ,Mitochondrial Dynamics ,GTP Phosphohydrolases ,Mitochondrial Proteins ,03 medical and health sciences ,DNM1L ,Fatal Outcome ,0302 clinical medicine ,medicine ,Humans ,Exome ,Family Health ,Genetics ,Microfilament Proteins ,Infant, Newborn ,Heterozygote advantage ,Hypotonia ,Pedigree ,INF2 ,030104 developmental biology ,Microscopy, Fluorescence ,Codon, Nonsense ,Mutation ,Pediatrics, Perinatology and Child Health ,Female ,Mitochondrial fission ,medicine.symptom ,Microtubule-Associated Proteins ,030217 neurology & neurosurgery - Abstract
We describe two infants with hypotonia, absent respiratory effort, and giant mitochondria in neurons due to compound heterozygosity for 2 nonsense mutations of DNM1L. DNM1L has a critical role in regulating mitochondrial morphology and function. This observation confirms the central role of mitochondrial fission to normal human development.
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- 2016
- Full Text
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