297 results on '"Kym M. Boycott"'
Search Results
52. Correspondence on 'cost or price of sequencing? implications for economic evaluations in genomic medicine' by Grosse and Gudgeon
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Stacey Vandersluis, Irfan A. Dhalla, Nancy Sikich, Corinne Holubowich, Vivian Ng, Wendy J. Ungar, Elaine Suk-Ying Goh, Kym M. Boycott, and Chunmei Li
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Genomic medicine ,Computational biology ,Biology ,Genetics (clinical) - Published
- 2022
53. A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset
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Meredith K. Gillespie, Hugh J. McMillan, Izabella A. Pena, Kym M. Boycott, Kristin D. Kernohan, Rebecca Meyer-Schuman, and Anthony Antonellis
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0301 basic medicine ,Neuromuscular disease ,Case Report ,Methionine-tRNA Ligase ,Disease ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Charcot-Marie-Tooth disease type 2U ,medicine ,Humans ,Child ,Gene ,Exome sequencing ,Genetics ,Genetic heterogeneity ,CMT2U ,MARS ,medicine.disease ,Phenotype ,Protein Structure, Tertiary ,3. Good health ,Congenital onset ,030104 developmental biology ,Neurology ,Mutation ,early-onset neuropathy ,Female ,Neurology (clinical) ,exome sequencing ,Novel mutation ,030217 neurology & neurosurgery - Abstract
Charcot-Marie-Tooth disease is a phenotypically and genetically heterogeneous group of disorders affecting both motor and sensory neurons. Exome sequencing has driven discovery of genes responsible for Charcot-Marie-Tooth disease with more than 70 genes now associated with this neuromuscular disease. The MARS gene was recently reported as the cause of Charcot-Marie-Tooth 2U, a slowly progressive axonal sensorimotor polyneuropathy with adult-onset reported in six patients. We report here a patient with a progressive, early childhood-onset, motor-predominant form of Charcot-Marie-Tooth disease. Exome sequencing identified a novel MARS variant (c.1189G>A; p.Ala397Thr) that was not present in her unaffected mother; her unaffected father was unavailable. Further studies using structural modeling and a yeast humanization assay support pathogenicity of the variant. Our study expands the phenotype of Charcot-Marie-Tooth 2U, while highlighting the utility of functional assays to evaluate variant pathogenicity.
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- 2019
54. Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities
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Jennifer A. Lee, Carlos Ferreira, Kym M. Boycott, Lina Basel-Salmon, Yue Si, Richard E. Person, Michael J. Lyons, Melissa T. Carter, Dmitriy Niyazov, Claudia Gonzaga-Jauregui, Renee Bend, Erin Torti, Lior Cohen, Samantha K Rojas, Ingrid M. Wentzensen, and Mohamad A. Mikati
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Male ,Microcephaly ,Adolescent ,Biology ,medicine.disease_cause ,Compound heterozygosity ,Article ,03 medical and health sciences ,Atrophy ,Genetics ,medicine ,Humans ,DNA sequencing ,Allele ,Child ,10. No inequality ,Genetics (clinical) ,Loss function ,0303 health sciences ,Mutation ,Neurodevelopmental disorders ,Medical genetics ,030305 genetics & heredity ,Brain ,Infant ,Protein Tyrosine Phosphatases, Non-Receptor ,medicine.disease ,Phenotype ,Child, Preschool ,Female ,Ventriculomegaly - Abstract
PTPN23 is a His-domain protein-tyrosine phosphatase implicated in ciliogenesis, the endosomal sorting complex required for transport (ESCRT) pathway, and RNA splicing. Until recently, no defined human phenotype had been associated with alterations in this gene. We identified and report a cohort of seven patients with either homozygous or compound heterozygous rare deleterious variants in PTPN23. Combined with four patients previously reported, a total of 11 patients with this disorder have now been identified. We expand the phenotypic and variation spectrum associated with defects in this gene. Patients have strong phenotypic overlap, suggesting a defined autosomal recessive syndrome caused by reduced function of PTPN23. Shared characteristics of affected individuals include developmental delay, brain abnormalities (mainly ventriculomegaly and/or brain atrophy), intellectual disability, spasticity, language disorder, microcephaly, optic atrophy, and seizures. We observe a broad range of variants across patients that are likely strongly reducing the expression or disrupting the function of the protein. However, we do not observe any patients with an allele combination predicted to result in complete loss of function of PTPN23, as this is likely incompatible with life, consistent with reported embryonic lethality in the mouse. None of the observed or reported variants are recurrent, although some have been identified in homozygosis in patients from consanguineous populations. This study expands the phenotypic and molecular spectrum of PTPN23 associated disease and identifies major shared features among patients affected with this disorder, while providing additional support to the important role of PTPN23 in human nervous and visual system development and function.
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- 2019
55. Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
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Diane B. Zastrow, Cameron J. Prybol, Jason D. Merker, Benjamin J. Strober, Euan A. Ashley, Zachary Zappala, Jennefer N. Kohler, Sowmithri Utiramerur, Chloe M. Reuter, Xin Li, Kevin S. Smith, Alexis Battle, Joe R. Davis, Craig Smail, Devon Bonner, Taila Hartley, Shruti Marwaha, Matthew T. Wheeler, Boxiang Liu, Stephen B. Montgomery, Nicole M. Ferraro, Lars Lind, Dianna G. Fisk, Brunilda Balliu, Nicole A. Teran, Erik Ingelsson, Laure Fresard, Gill Bejerano, Megan E. Grove, Ruchi Joshi, Kym M. Boycott, Jonathan A. Bernstein, Kristin D. Kernohan, and Jean M. Davidson
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Male ,0301 basic medicine ,Oxidoreductases Acting on CH-CH Group Donors ,Candidate gene ,medicine.medical_specialty ,Potassium Channels ,Acid Ceramidase ,RNA Splicing ,Disease ,Biology ,Bioinformatics ,Article ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,Cohort Studies ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Exome Sequencing ,medicine ,Humans ,Child ,Exome sequencing ,Models, Genetic ,Sequence Analysis, RNA ,Case-control study ,Genetic Variation ,General Medicine ,Disease gene identification ,3. Good health ,030104 developmental biology ,Case-Control Studies ,Child, Preschool ,030220 oncology & carcinogenesis ,Mutation ,RNA ,Medical genetics ,Female ,Rare disease - Abstract
It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2–5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6–8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution. A diagnostic tool based on blood RNA-seq is shown to identify causal genes and variants linked to clinical phenotypes in individuals with rare diseases for which whole-exome genetic sequencing was uninformative.
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- 2019
56. Direct health-care costs for children diagnosed with genetic diseases are significantly higher than for children with other chronic diseases
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Taila Hartley, Alison B. Hamilton, Heather E Howley, Daniel Rodriguez Duque, Faheem Malam, Deborah A. Marshall, Meredith K. Gillespie, Eric I Benchimol, Kym M. Boycott, Karen V. MacDonald, and Alex MacKenzie
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0301 basic medicine ,education.field_of_study ,Pediatrics ,medicine.medical_specialty ,business.industry ,Total cost ,Population ,Retrospective cohort study ,Disease ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030225 pediatrics ,Diabetes mellitus ,Cohort ,Health care ,medicine ,education ,business ,health care economics and organizations ,Genetics (clinical) ,Asthma - Abstract
We aimed to estimate direct health-care costs and physician utilization for a cohort of children diagnosed with genetic diseases. Retrospective cohort study using population-based provincial health administrative data for children with genetic diseases (n = 255) compared with three matched cohorts (asthma n = 1275, diabetes n = 255, general population n = 1275). We estimated direct health-care costs and resource use 5 years after diagnosis in five categories: physician billing, same day surgery, emergency, inpatient hospitalizations, and home care. During the postdiagnostic period, annual mean total costs for the genetic disease cohort were significantly higher than all other cohorts. Annual mean total costs for all cohorts were highest in the year after diagnosis with costs for the genetic disease cohort between 4.54 and 19.76 times higher during the 5 years. Inpatient hospitalizations and physician billing accounted for the majority of costs. The genetic disease cohort received more care from specialists, whereas the chronic disease cohorts received more care from general practitioners. Direct health-care costs for children with genetic diseases are significantly higher than children with/without a chronic disease, particularly in the year after diagnosis. These findings are important when considering resource allocation and funding prioritization for children with genetic diseases.
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- 2019
57. Clinical delineation of GTPBP2 ‐associated neuro‐ectodermal syndrome: Report of two new families and review of the literature
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Kym M. Boycott, Sunita Venkateswaran, Peter Humphreys, Gali Shapira-Zaltsberg, Jorge Davila, Melissa T. Carter, and Kristin D. Kernohan
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0301 basic medicine ,Microcephaly ,Ectodermal dysplasia ,Movement disorders ,media_common.quotation_subject ,Nonsense ,Context (language use) ,030105 genetics & heredity ,Compound heterozygosity ,Bioinformatics ,03 medical and health sciences ,Epilepsy ,GTP-Binding Proteins ,Ectoderm ,Exome Sequencing ,Genetics ,medicine ,Humans ,Family ,Genetics (clinical) ,media_common ,business.industry ,Syndrome ,medicine.disease ,3. Good health ,030104 developmental biology ,Peripheral neuropathy ,medicine.symptom ,business - Abstract
The GTPBP2 gene encodes a guanosine triphosphate (GTP)-binding protein of unknown function. Biallelic loss-of-function variants in the GTPBP2 gene have been previously reported in association with a neuro-ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age-related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.
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- 2019
58. Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis
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Eric Bareke, David Grynspan, Jean Michaud, Danielle K Bourque, Mireille Cloutier, Kristin D. Kernohan, and Kym M. Boycott
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0301 basic medicine ,Arthrogryposis ,Microcephaly ,Pathology ,medicine.medical_specialty ,business.industry ,Cystic hygroma ,Prenatal diagnosis ,030105 genetics & heredity ,medicine.disease ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,Lymphangioma ,Genetics ,medicine ,Neu-Laxova syndrome ,medicine.symptom ,business ,Increased nuchal translucency ,Genetics (clinical) ,Exome sequencing - Abstract
Neu-Laxova syndrome (NLS) is a lethal autosomal recessive microcephaly syndrome associated with intrauterine growth restriction (IUGR) and multiple congenital anomalies. Clinical features include central nervous system malformations, joint contractures, ichthyosis, edema, and dysmorphic facial features. Biallelic pathogenic variants in either the PHGDH or PSAT1 genes have been shown to cause NLS. Using exome sequencing, we aimed to identify the underlying genetic diagnosis in three fetuses (from one family) with prenatal skin edema, severe IUGR, micrognathia, renal anomalies, and arthrogryposis and identified a homozygous c.1A>C (p.Met1?, NM_006623.3) variant in the PHGDH gene. Loss of the translation start codon is a novel genetic mechanism for the development of NLS. Prenatal diagnosis of NLS is challenging and few reports describe the fetal pathology. Fetal neuropathologic examination revealed: delayed brain development, congenital agenesis of the corticospinal tracts, and hypoplasia of the hippocampus, cerebellum and brainstem. Each pregnancy also showed increased nuchal translucency (NT) or cystic hygroma. While NLS is rare, it may be a cause of recurrent increased NT/cystic hygroma. This finding provides further support that cystic hygroma has many different genetic causes and that exome sequencing may shed light on the underlying genetic diagnoses in this group of prenatal patients.
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- 2019
59. Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes
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Zejuan Li, Erin Sandford, Viswateja Nelakuditi, Miao Sun, Kym M. Boycott, Jodi Warman Chardon, Lan Ma, Daniela del Gaudio, Vikram G. Shakkottai, Kelly Arndt, Soma Das, David Fischer, Darrel Waggoner, Lucia Guidugli, Margit Burmeister, Christopher M. Gomez, and Amy K. Johnson
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Ataxia ,business.industry ,Disease ,030105 genetics & heredity ,Human genetics ,03 medical and health sciences ,030104 developmental biology ,Internal medicine ,Molecular genetics ,Etiology ,Medicine ,medicine.symptom ,business ,Exome ,Genetics (clinical) ,ADCK3 ,Exome sequencing - Abstract
To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes. One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patients ranged in age from 2 to 88 years. Analysis was focused on 441 curated genes associated with ataxia and ataxia-like conditions. Pathogenic and suspected diagnostic variants were identified in 88 of the 170 patients, providing a positive molecular diagnostic rate of 52%. Forty-six different genes were implicated, with the six most commonly mutated genes being SPG7, SYNE1, ADCK3, CACNA1A, ATP1A3, and SPTBN2, which accounted for >40% of the positive cases. In many cases a diagnosis was provided for conditions that were not suspected and resulted in the broadening of the clinical spectrum of several conditions. Exome sequencing with targeted analysis provides a high-yield approach for the genetic diagnosis of ataxia-related conditions. This is the largest targeted exome study performed to date in patients with ataxia and ataxia-like conditions and represents patients with a wide range of ataxia phenotypes typically encountered in neurology and genetics clinics.
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- 2019
60. A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome
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Kristin D. Kernohan, Sara Ellingwood, Jaime Barea, Christoffer Nellåker, Simon Sadedin, Katrin Õunap, Taila Hartley, Margarete Koch-Hogrebe, Marjan M. Nezarati, Augusta M. A. Lachmeijer, Dagmar Wieczorek, Elizabeth J. Bhoj, Paul J. Lockhart, Kym M. Boycott, Aren E Marshall, Tiong Yang Tan, Sander Pajusalu, Arran McBride, John Christodoulou, Michelle E. Ernst, Alison S May, Rami Abou Jamra, Susan M. White, Dong Li, K.L.I. van Gassen, and Wendy E. Smith
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Male ,Adolescent ,DNA Repair ,DNA damage ,DNA repair ,medicine.disease_cause ,Chromatin remodeling ,03 medical and health sciences ,DDB1 ,Report ,Histone methylation ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,Alleles ,030304 developmental biology ,0303 health sciences ,Mutation ,biology ,030305 genetics & heredity ,Syndrome ,Hypotonia ,Ubiquitin ligase ,DNA-Binding Proteins ,Phenotype ,Neurodevelopmental Disorders ,Child, Preschool ,biology.protein ,Female ,medicine.symptom - Abstract
The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. The affected individuals have a consistent phenotype of hypotonia, mild to moderate intellectual disability, and similar facies, including horizontal or slightly bowed eyebrows, deep-set eyes, full cheeks, a short nose, and large, fleshy and forward-facing earlobes, demonstrated in the composite face generated from the cohort. Digital anomalies, including brachydactyly and syndactyly, were common. Three older individuals have obesity. We show that cells derived from affected individuals have altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage. Overall, our study adds to the growing family of neurodevelopmental phenotypes mediated by disruption of the CRL4 ubiquitin ligase pathway and begins to delineate the phenotypic and molecular effects of DDB1 misregulation.
- Published
- 2021
61. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females
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Gilles Morin, Krista Bluske, Nathaniel H. Robin, Laurence Faivre, Manuela Priolo, Dihong Zhou, Evangeline Kurtz-Nelson, Tianyun Wang, Omar Sherbini, Daryl A. Scott, Karen Stals, Fabíola Paoli Monteiro, Kaifang Pang, Sara Cabet, Francesca Clementina Radio, Bruno Dallapiccola, Marjon van Slegtenhorst, Rachel K. Earl, Katheryn Grand, Maria Iascone, Alice S. Brooks, Angelo Selicorni, July K. Jean Cuevas, Paolo Gasparini, Maria Lisa Dentici, Marialetizia Motta, Britt-Marie Anderlid, Kristin Lindstrom, Berrin Monteleone, Andrea Ciolfi, Karin Weiss, Katharina Steindl, Kirsty McWalter, Rosalba Carrozzo, Ruben Boers, Helen Kingston, Kym M. Boycott, Bekim Sadikovic, Laura Schultz-Rogers, Evan E. Eichler, Laura A Cross, Alison M R Castle, Louisa Kalsner, Lucia Pedace, Marijke R. Wevers, John M. Graham, Jessica Sebastian, Antonio Vitobello, Gaetan Lesca, Alexander P.A. Stegmann, Suneeta Madan-Khetarpal, Tahsin Stefan Barakat, Abdallah F. Elias, Teresa Robert Finestra, Adeline Vanderver, Peter D. Turnpenny, Bregje W.M. van Bon, Aida Telegrafi, David J. Amor, Deepali N. Shinde, Pedro A. Sanchez-Lara, Lisenka E.L.M. Vissers, Adam Jackson, Rolph Pfundt, Alessandro Bruselles, Andres Hernandez-Garcia, Karin E. M. Diderich, Flavio Faletra, Dana H. Goodloe, Joanne Baez, Sarit Ravid, Romano Tenconi, Sarah L. Sawyer, Lynn Pais, Bronwyn Kerr, Joost Gribnau, Lauren Carter, Melissa T. Carter, Zhandong Liu, Jennifer L. Kemppainen, Jennifer MacKenzie, Jimmy Holder, Elke de Boer, Margaret Au, Taila Hartley, Carol J Saunders, Luciana Musante, Bert B.A. de Vries, Tania Vertemati Secches, Haley McConkey, Willow Sheehan, Francesca Pantaleoni, Caterina Zanus, Christophe Philippe, Chelsea Roadhouse, Stefania Lo Cicero, Sian Ellard, R. Tanner Hagelstrom, Megha Desai, Fernando Kok, Joset Pascal, Marco Tartaglia, Eric W. Klee, Eva Morava, Michael A. Levy, Peggy Kulch, Lyndon Gallacher, Erica L. Macke, Emilia Stellacci, Siddharth Banka, Kristin G. Monaghan, Anita Rauch, Meghan C. Towne, Kate Chandler, Clinical Genetics, Developmental Biology, Radio, F. C., Pang, K., Ciolfi, A., Levy, M. A., Hernandez-Garcia, A., Pedace, L., Pantaleoni, F., Liu, Z., de Boer, E., Jackson, A., Bruselles, A., Mcconkey, H., Stellacci, E., Lo Cicero, S., Motta, M., Carrozzo, R., Dentici, M. L., Mcwalter, K., Desai, M., Monaghan, K. G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P. A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., Mackenzie, J. J., Monteleone, B., Saunders, C. J., Jean Cuevas, J. K., Cross, L., Zhou, D., Hartley, T., Sawyer, S. L., Monteiro, F. P., Secches, T. V., Kok, F., Schultz-Rogers, L. E., Macke, E. L., Morava, E., Klee, E. W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D. J., Pais, L., Gallacher, L., Turnpenny, P. D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A. M. R., Carter, M. T., Kalsner, L., de Vries, B. B. A., van Bon, B. W., Wevers, M. R., Pfundt, R., Stegmann, A. P. A., Kerr, B., Kingston, H. M., Chandler, K. E., Sheehan, W., Elias, A. F., Shinde, D. N., Towne, M. C., Robin, N. H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R. T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E. C., Earl, R. K., Anderlid, B. -M., Morin, G., van Slegtenhorst, M., Diderich, K. E. M., Brooks, A. S., Gribnau, J., Boers, R. G., Finestra, T. R., Carter, L. B., Rauch, A., Gasparini, P., Boycott, K. M., Barakat, T. S., Graham, J. M., Faivre, L., Banka, S., Wang, T., Eichler, E. E., Priolo, M., Dallapiccola, B., Vissers, L. E. L. M., Sadikovic, B., Scott, D. A., Holder, J. L., Tartaglia, M., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output
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0301 basic medicine ,SHARP ,Male ,obesity ,genotype-phenotype correlations ,Autism Spectrum Disorder ,PROTEIN ,Chromosome Disorders ,Haploinsufficiency ,RNA-Binding Protein ,PHENOTYPE CORRELATIONS ,1p36 ,distal 1p36 deletion syndrome ,DNA methylome analysis ,episignature ,neurodevelopmental disorder ,proximal 1p36 deletion syndrome ,SPEN ,X chromosome ,Adolescent ,Child ,Child, Preschool ,Chromosome Deletion ,Chromosomes, Human, Pair 1 ,Chromosomes, Human, X ,DNA Methylation ,DNA-Binding Proteins ,Epigenesis, Genetic ,Female ,Humans ,Intellectual Disability ,Neurodevelopmental Disorders ,Phenotype ,RNA-Binding Proteins ,Young Adult ,0302 clinical medicine ,Neurodevelopmental disorder ,Neurodevelopmental Disorder ,Intellectual disability ,MOLECULAR CHARACTERIZATION ,Genetics (clinical) ,Genetics ,DNA methylome analysi ,SPLIT-ENDS ,Hypotonia ,Autism spectrum disorder ,MONOSOMY 1P36 ,Pair 1 ,medicine.symptom ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Human ,DNA-Binding Protein ,Biology ,genotype-phenotype correlation ,Chromosomes ,03 medical and health sciences ,Genetic ,SDG 3 - Good Health and Well-being ,Report ,REVEALS ,medicine ,Epigenetics ,Preschool ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,1p36 deletion syndrome ,IDENTIFICATION ,MUTATIONS ,medicine.disease ,GENE ,030104 developmental biology ,Chromosome Disorder ,030217 neurology & neurosurgery ,Epigenesis - Abstract
Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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- 2021
62. Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development
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Christopher Kelly, Brenda J. Barry, Kym M. Boycott, Wai-Man Chan, Daniel G. MacArthur, Sarah MacKinnon, Julie Jurgens, Anne H. O’Donnell-Luria, Hugh J. McMillan, David G. Hunter, Mary C. Whitman, Sherin Shaaban, Brandon M Pratt, Gabrielle Lemire, Elizabeth C. Engle, Eleina M. England, and Caroline D. Robson
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Proband ,Male ,Heterozygote ,Adolescent ,Mutation, Missense ,Kinesins ,Biology ,DNA sequencing ,Article ,Lateral ventricles ,Tubulin ,Congenital fibrosis of the extraocular muscles ,Genetics ,medicine ,Missense mutation ,Humans ,Child ,Gene ,Genetics (clinical) ,Exome sequencing ,TUBB3 ,Binding Sites ,Ophthalmoplegia ,medicine.disease ,Fibrosis ,Malformations of Cortical Development ,Female - Abstract
Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.
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- 2021
63. Author response for 'Whole genome sequencing reveals biallelic PLA2G6 mutations in siblings with cerebellar atrophy and cap myopathy'
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Aren E Marshall, Hugh J. McMillan, Sunita Venkateswaran, Jodi Warman-Chardon, Jean Michaud, Kristin D. Kernohan, Taila Hartley, Christian R. Marshall, David A. Dyment, Kym M. Boycott, and Arun K. Ramani
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Genetics ,Whole genome sequencing ,Cerebellar atrophy ,Biology ,Cap myopathy - Published
- 2021
64. Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome
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Sixto Garcia Minaur, Pankaj B. Agrawal, A. Micheil Innes, Catherine A. Brownstein, David S. Wargowski, Brenda McInnes, Isaac Wong, Albert E. Chudley, Jennifer E. Posey, Francesc López-Giráldez, Ping-Yee B Au, Alper Gezdirici, Kyrieckos A. Aleck, Eric Boerwinkle, Paolo Prontera, Bilgen Bilge Geçkinli, Yeting Zhang, An Nguyen, David A. Dyment, Jukka S. Moilanen, Alan H. Beggs, Nara Sobreira, Hatip Aydin, Elizabeth E. Blue, Kathryn Dunn, Gerald F. Cox, Bernard N. Chodirker, Harrison Brand, Jinchuan Xing, Hind Al Sharhan, Bert B.A. de Vries, Maria Juliana Rodovalho Doriqui, Davut Pehlivan, Shalini N. Jhangiani, Centers for Mendelian Genomics, Katrin Õunap, Cheryl R. Greenberg, Kaya Bilguvar, Carol L. Clericuzio, Cynthia J. Curry, Taila Hartley, Julie Lauzon, Michael J. Bamshad, Timothy Poterba, R. Brian Lowry, Jill A. Fahrner, Cullen M. Dutmer, M. E. Suzanne Lewis, Steve Buyske, Ender Karaca, Aziz Mhanni, William T. Gibson, Valentina Stanley, April Hall, Elke de Boer, Kristin D. Kernohan, Joseph G. Gleeson, P. Dane Witmer, Jungmin Choi, Danny Antaki, Małgorzata J.M. Nowaczyk, Sander Pajusalu, Anne H. O’Donnell-Luria, Sarah L. Sawyer, Zeynep Coban Akdemir, Tara C. Matise, Jennifer McEvoy-Venneri, Casie A. Genetti, Kym M. Boycott, Lynette S. Penney, Ada Hamosh, Eleina M. England, Deniz Torun, Maha S. Zaki, Deborah A. Nickerson, Dyment, David A., O'Donnell-Luria, Anne, Agrawal, Pankaj B., Coban Akdemir, Zeynep, Aleck, Kyrieckos A., Antaki, Danny, Al Sharhan, Hind, Au, Ping-Yee B., Aydin, Hatip, Beggs, Alan H., Bilguvar, Kaya, Boerwinkle, Eric, Brand, Harrison, Brownstein, Catherine A., Buyske, Steve, Chodirker, Bernard, Choi, Jungmin, Chudley, Albert E., Clericuzio, Carol L., Cox, Gerald F., Curry, Cynthia, de Boer, Elke, de Vries, Bert B. A., Dunn, Kathryn, Dutmer, Cullen M., England, Eleina M., Fahrner, Jill A., Geckinli, Bilgen B., Genetti, Casie A., Gezdirici, Alper, Gibson, William T., Gleeson, Joseph G., Greenberg, Cheryl R., Hall, April, Hamosh, Ada, Hartley, Taila, Jhangiani, Shalini N., Karaca, Ender, Kernohan, Kristin, Lauzon, Julie L., Lewis, M. E. Suzanne, Lowry, R. Brian, Lopez-Giraldez, Francesc, Matise, Tara C., McEvoy-Venneri, Jennifer, McInnes, Brenda, Mhanni, Aziz, Garcia Minaur, Sixto, Moilanen, Jukka, Nguyen, An, Nowaczyk, Malgorzata J. M., Posey, Jennifer E., Ounap, Katrin, Pehlivan, Davut, Pajusalu, Sander, Penney, Lynette S., Poterba, Timothy, Prontera, Paolo, Doriqui, Maria Juliana Rodovalho, Sawyer, Sarah L., Sobreira, Nara, Stanley, Valentina, Torun, Deniz, Wargowski, David, Witmer, P. Dane, Wong, Isaac, Xing, Jinchuan, Zaki, Maha S., Zhang, Yeting, Boycott, Kym M., Bamshad, Michael J., Nickerson, Deborah A., Blue, Elizabeth E., and Innes, A. Micheil
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0301 basic medicine ,Male ,ANOMALIES ,INTELLECTUAL DISABILITY ,Eczema ,030105 genetics & heredity ,PHENOTYPE ,genetic heterogeneity ,Locus heterogeneity ,Dubowitz syndrome ,Exome ,Child ,Genetics (clinical) ,Exome sequencing ,Growth Disorders ,Genetics ,FRAMESHIFT ,Genomics ,3. Good health ,VPS13B ,genome sequencing ,LOSS-OF-FUNCTION ,Child, Preschool ,symbols ,Microcephaly ,Female ,microarray ,Adolescent ,DNA Copy Number Variations ,Biology ,NSUN2 ,PATIENT ,DNA sequencing ,Histone Deacetylases ,Article ,03 medical and health sciences ,symbols.namesake ,medicine ,Humans ,Genetic Predisposition to Disease ,ANEMIA ,Genetic heterogeneity ,Genome, Human ,MUTATIONS ,Facies ,Infant ,PLATFORM ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,Mendelian inheritance ,exome sequencing - Abstract
Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
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- 2021
65. The International Rare Diseases Research Consortium : Policies and Guidelines to maximize impact
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Anneliene H. Jonker, Yann Le Cam, Josep Torrent i Farnell, Gareth Baynam, Hugh Dawkins, Christopher P. Austin, Lilian P.L. Lau, Hanns Lochmüller, Paul Lasko, Kym M. Boycott, and Petra Kaufmann
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0301 basic medicine ,business.industry ,International Cooperation ,Environmental resource management ,Guidelines as Topic ,Human Genetics ,030105 genetics & heredity ,Intellectual property ,Public relations ,Medical research ,Biobank ,Transparency (behavior) ,Article ,3. Good health ,Data sharing ,03 medical and health sciences ,Rare Diseases ,Genetics ,Humans ,Business ,Productivity ,Genetics (clinical) ,Health policy ,Rare disease - Abstract
Altres ajuts: This work and the IRDiRC Scientific Secretariat are supported by the European FP7 contract, "SUPPORT-IRDiRC" (No 305207). H.L. receives funding from the European Commission under FP7 through NeurOmics (No 305121) and RD-Connect (No 305444). C.P.A. contributed to this work in his capacity as Chair of the IRDiRC Consortium Assembly, not as Director of the NCATS. The remaining authors declare that they have no competing interests. The International Rare Diseases Research Consortium (IRDiRC) has agreed on IRDiRC Policies and Guidelines, following extensive deliberations and discussions in 2012 and 2013, as a first step towards improving coordination of research efforts worldwide. The 25 funding members and 3 patient umbrella organizations (as of early 2013) of IRDiRC, a consortium of research funders that focuses on improving diagnosis and therapy for rare disease patients, agreed in Dublin, Ireland in April 2013 on the Policies and Guidelines that emphasize collaboration in rare disease research, the involvement of patients and their representatives in all relevant aspects of research, as well as the sharing of data and resources. The Policies and Guidelines provide guidance on ontologies, diagnostics, biomarkers, patient registries, biobanks, natural history, therapeutics, models, publication, intellectual property, and communication. Most IRDiRC members-currently nearly 50 strong-have since incorporated its policies in their funding calls and some have chosen to exceed the requirements laid out, for instance in relation to data sharing. The IRDiRC Policies and Guidelines are the first, detailed agreement of major public and private funding organizations worldwide to govern rare disease research, and may serve as a template for other areas of international research collaboration. While it is too early to assess their full impact on research productivity and patient benefit, the IRDiRC Policies and Guidelines have already contributed significantly to improving transparency and collaboration in rare disease research.
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- 2021
66. Germline AGO2 mutations impair RNA interference and human neurological development
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Ee-Shien Tan, John Pappas, Tiffany Busa, Marjolein H. Willemsen, Erica H. Gerkes, Astrid Bruckmann, Linda Ramsdell, Davor Lessel, Chieko Chijiwa, Diana Mitter, Ghayda M. Mirzaa, Peter Ian Andrews, Daniela M. Zeitler, Claudia Schob, Pankaj Prasun, M. E. Suzanne Lewis, Rami Abou Jamra, Andriy Kazantsev, Aida Telegrafi, Steffen Syrbe, Chantal Missirian, Victoria Martens, Kimberly Foss, Margot R.F. Reijnders, Bianca Panis, Ilaria Mannucci, Bernarda Lozić, Fatemeh Hassani Nia, Rolph Pfundt, Tanja Kovacevic, Han G. Brunner, Christian Kubisch, Allyn McConkie-Rosell, Breana Cham, Gunter Meister, Jessika Johannsen, Veronika Graus, Henny H. Lemmink, Stefan Kindler, Jonas Denecke, Kirsty McWalter, Ivana Lessel, Zoya Ignatova, Hans-Jürgen Kreienkamp, Matthew Osmond, Thatjana Gardeitchik, Alexander P.A. Stegmann, Rachel Rabin, Alexander Bartholomäus, Jérémie Mortreux, Katharina Löhner, Tony Roscioli, Tjitske Kleefstra, Taila Hartley, Andreas Merkenschlager, Patrick Rump, Marie T. McDonald, Kym M. Boycott, Evelien Zonneveld-Huijssoon, David A. Dyment, Carey-Anne Evans, Margje Sinnema, Sabine Lüttgen, Joanna Lazier, Diana Le Duc, Kerith-Rae Dias, Ene-Choo Tan, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE16-0025,MicroRNAct,Identification de complexes microARN/mARN fonctionnels dans le cerveau antérieur de souris: de la neurogenèse au comportement et à la pathologie(2017), MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
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0301 basic medicine ,INTELLECTUAL DISABILITY ,MICRORNAS ,[SDV]Life Sciences [q-bio] ,molecular-dynamics ,General Physics and Astronomy ,ARGONAUTE-2, ARGONAUTE-2 ,Hippocampus ,Nervous System ,Transcriptome ,Mice ,0302 clinical medicine ,RNA interference ,Cluster Analysis ,Phosphorylation ,RNA, Small Interfering ,lcsh:Science ,Child ,Regulation of gene expression ,Neurons ,Multidisciplinary ,Molecular medicine ,Neurodevelopmental disorders ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,3. Good health ,Cell biology ,Child, Preschool ,Argonaute Proteins ,RNA Interference ,STRUCTURAL BASIS ,Adolescent ,Science ,Biology ,Molecular Dynamics Simulation ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Protein Domains ,microRNA ,Gene silencing ,Animals ,Humans ,RNA-Induced Silencing Complex ,Gene Silencing ,RNA, Messenger ,Messenger RNA ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,CLEAVAGE ,HEK 293 cells ,RECOGNITION ,crystal-structure ,RNA ,General Chemistry ,Dendrites ,Fibroblasts ,GENE ,Rats ,030104 developmental biology ,Germ Cells ,HEK293 Cells ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Mutation ,lcsh:Q ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030217 neurology & neurosurgery - Abstract
ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development., AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.
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- 2020
67. Multi-omics approach characterises CRLS1 deficiency, a novel mitochondrial disorder
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Shanti Balasubramaniam, Richard G. Lee, Benjamin Padman, Kym M. Boycott, Michael T. Geraghty, Rebecca Walsh, Sasha Ferdinandusse, Oliver Rackham, Frédéric M. Vaz, Tony Rosciolli, Gavin E. Reid, Janice Fletcher, and Aleksandra Filipovska
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Pathology and Forensic Medicine - Published
- 2022
68. Evidence for non-Mendelian inheritance in spastic paraplegia 7
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Patrick A. Dion, Ikhlass Haj Salem, Kym M. Boycott, Nicolas Dupré, Oksana Suchowersky, Ziv Gan-Or, Alain Dagher, Fulya Akçimen, Eric Yu, Mehrdad Asghari Estiar, Mark A. Tarnopolsky, Jay P. Ross, Grace Yoon, Jennifer A. Ruskey, Farnaz Asayesh, Kheireddin Mufti, Dan Spiegelman, Jean-François Trempe, Guy A. Rouleau, and Etienne Leveille
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Genetics ,Non-Mendelian inheritance ,Hereditary spastic paraplegia ,Biology ,medicine.disease ,Digenic inheritance ,nervous system diseases ,symbols.namesake ,Spastic ,Mendelian inheritance ,symbols ,medicine ,Spinocerebellar ataxia ,Spastic paraplegia type 7 ,Exome sequencing - Abstract
Hereditary spastic paraplegia is a group of rare motor neuron diseases considered to be inherited in a classical monogenic Mendelian manner. Although the typical inheritance of spastic paraplegia type 7 is autosomal recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant HSP. We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of hereditary spastic paraplegia patients and controls to examine the association of SPG7 and hereditary spastic paraplegia. In total, 585 hereditary spastic paraplegia patients from 372 families and 1,175 controls, including 580 unrelated individuals, were analyzed for the presence of SPG7 variants. Whole exome sequencing was performed on 400 hereditary spastic paraplegia patients (291 index cases) and all 1,175 controls. After excluding 38 biallelic hereditary spastic paraplegia type 7 patients, the frequency of heterozygous pathogenic/likely pathogenic SPG7 variant carriers (4.8%) among hereditary spastic paraplegia unrelated index cases who underwent WES, was significantly higher than among unrelated controls (1.7%; OR=2.88, 95%CI=1.24-6.66, p=0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index cases vs. 0.85% in unrelated controls (OR=4.42, 95%CI=1.49-13.07, p=0.005). We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in genes known to cause hereditary spastic paraplegia, compared to zero in controls (OR=19.58, 95%CI=1.05-365.13, p=0.0031; Fisher’s Exact test with Haldane-Anscombe correction), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2 and MORC2). Out of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. Our results provide evidence for complex inheritance in SPG7-associated hereditary spastic paraplegia, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance.
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- 2020
69. Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans
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Mais Hashem, Moeenaldeen Al-Sayed, Mohamed H Al-Hamed, Maha Alnemer, Wenkai Han, Mohamed Tohary, Yongkang Long, Almundher Al-Maawali, Feisal Al Mahrizi, Xin Gao, Khalid Al-Thihli, Fowzan S. Alkuraya, Hiroyuki Kuwahara, Gabrielle Lemire, Lana Fathi, Kym M. Boycott, Fatema Alzahrani, Mohammed Al-Owain, and Mohammed Mahnashi
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Heart Defects, Congenital ,Male ,Microcephaly ,Adolescent ,Genetic Linkage ,Developmental Disabilities ,Nonsense-mediated decay ,RNA-Seq ,Biology ,03 medical and health sciences ,Consanguinity ,Young Adult ,0302 clinical medicine ,Report ,Intellectual disability ,Genetics ,medicine ,Humans ,Global developmental delay ,RNA, Messenger ,Kinase activity ,Phosphorylation ,Child ,Genetics (clinical) ,030304 developmental biology ,Family Health ,0303 health sciences ,Homozygote ,Intracellular Signaling Peptides and Proteins ,Brain ,Infant ,medicine.disease ,Phenotype ,Nonsense Mediated mRNA Decay ,Pedigree ,Child, Preschool ,Trans-Activators ,Female ,030217 neurology & neurosurgery ,Gene Deletion ,RNA Helicases - Abstract
Summary We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.
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- 2020
70. Channelopathies Are a Frequent Cause of Genetic Ataxias Associated with Cerebellar Atrophy
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David A. Dyment, Kym M. Boycott, Bernard Brais, Laurence Gauquelin, Sohnee Ahmed, Jacek Majewski, Mark A. Tarnopolsky, Allan Micheil Innes, Martine Tétreault, Samantha K Rojas, Guy A. Rouleau, Francois P. Bernier, Karine Choquet, Michael T. Geraghty, Oksana Suchowersky, Grace Yoon, and Taila Hartley
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0301 basic medicine ,Disease gene ,Pediatrics ,medicine.medical_specialty ,Ataxia ,business.industry ,030105 genetics & heredity ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Neurology ,Cohort ,medicine ,Cerebellar atrophy ,Neurology (clinical) ,Medical diagnosis ,medicine.symptom ,Prospective cohort study ,business ,Genetic diagnosis ,030217 neurology & neurosurgery ,Exome sequencing ,Research Articles - Abstract
Background Cerebellar atrophy is a nonspecific imaging finding observed in a number of neurological disorders. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of conditions, rendering the approach to diagnosis challenging. Objectives To define the spectrum of genetic ataxias associated with cerebellar atrophy in a Canadian cohort and the diagnostic yield of exome sequencing for this group of conditions. Methods A total of 92 participants from 66 families with cerebellar atrophy were recruited for this multicenter prospective cohort study. Exome sequencing was performed for all participants between 2011 and 2017 as part of 1 of 2 national research programs, Finding of Rare Genetic Disease Genes or Enhanced Care for Rare Genetic Diseases in Canada. Results A genetic diagnosis was established in 53% of families (35/66). Pathogenic variants were found in 21 known genes, providing a diagnosis for 31/35 families (89%), and in 4 novel genes, accounting for 4/35 families (11%). Of the families, 31/66 (47%) remained without a genetic diagnosis. The most common diagnoses were channelopathies, which were established in 9/35 families (26%). Additional clinical findings provided useful clues to specific diagnoses. Conclusions We report on the high frequency of channelopathies as a cause of genetic ataxias associated with cerebellar atrophy and the utility of exome sequencing for this group of conditions.
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- 2020
71. New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases
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Heather E. Howley, Taila Hartley, Kym M. Boycott, David R. Adams, Kristin D. Kernohan, and Gabrielle Lemire
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medicine.medical_specialty ,business.industry ,Genome, Human ,Cornerstone ,Genomics ,Disease ,Data sharing ,Rare Diseases ,Genetics ,Medicine ,Humans ,business ,Intensive care medicine ,Molecular Biology ,Genetics (clinical) - Abstract
Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale.
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- 2020
72. Author response for 'When to think outside the autozygome: Best practices for exome sequencing in 'consanguineous' families'
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A. Micheil Innes, Taila Hartley, CareRare Canada, Alison Eaton, Ryan E. Lamont, Yoko Ito, Kristin D. Kernohan, Nick Barrowman, J.S. Parboosingh, and Kym M. Boycott
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Best practice ,Sociology ,Genealogy ,Exome sequencing - Published
- 2020
73. The Deep Genome Project
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Martin Hrabé de Angelis, Radislav Sedlacek, Paul Flicek, Sara Wells, Ann-Marie Mallon, James R. Lupski, Jason D. Heaney, Calum A. MacRae, Gareth Baynam, Michael S. Pepper, Mark J. Caulfield, Stanislas Lyonnet, Kevin C K Lloyd, Ying Xu, Stephen A. Murray, Arthur L. Beaudet, Yann Herault, David Valle, Chi-Kuang Leo Wang, Yuichi Obata, David J. Adams, Michael S. Dobbie, Damian Smedley, Mary E. Dickinson, Fatima Bosch, Roderick R. McInnes, Wolfgang Wurst, Robert Braun, Anne Grobler, Lauryl M. J. Nutter, Glauco P. Tocchini-Valentini, Helen Parkinson, Terrence F. Meehan, Ann M Flenniken, Sanjeev Galande, Fabio Mammano, Je Kyung Seong, Kym M. Boycott, Ronald Cohn, Colin McKerlie, Xiang Gao, Toshihiko Shiroishi, Jacqueline K. White, Steve D. M. Brown, University of California [Davis] (UC Davis), University of California, Genetic Services of Western Australia, King Edward Memorial Hospital [Mumbai], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Department of Biochemistry and Molecular Biology [Bellaterra, Spain], Universitat Autònoma de Barcelona (UAB)-School of Veterinary Medicine [Bellaterra, Spain], University of Ottawa [Ottawa], Centre National de la Recherche Scientifique (CNRS), and 11008857 - Grobler, Anne Frederica
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lcsh:QH426-470 ,Bioinformatics ,In silico ,[SDV]Life Sciences [q-bio] ,ved/biology.organism_classification_rank.species ,Computational biology ,Biology ,VARIANTS ,MOUSE ,Genome ,DNA sequencing ,null mutations ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genome editing ,ddc:570 ,Information and Computing Sciences ,Animals ,Humans ,mouse models ,Model organism ,lcsh:QH301-705.5 ,Gene ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,ved/biology ,Proteins ,Genome project ,Biological Sciences ,genetics [Proteins] ,Human genetics ,3. Good health ,lcsh:Genetics ,Editorial ,Phenotype ,lcsh:Biology (General) ,Genes ,Mutation ,genetics [Mice] ,International Mouse Phenotyping Consortium ,functional genomics ,030217 neurology & neurosurgery ,Environmental Sciences - Abstract
In vivo research is critical to the functional dissection of multi-organ systems and whole organism physiology, and the laboratory mouse remains a quintessential animal model for studying mammalian, especially human, pathobiology. Enabled by technological innovations in genome sequencing, mutagenesis and genome editing, phenotype analyses, and bioinformatics, in vivo analysis of gene function and dysfunction in the mouse has delivered new understanding of the mechanisms of disease and accelerated medical advances. However, many significant hurdles have limited the elucidation of mechanisms underlying both rare and complex, multifactorial diseases, leaving significant gaps in our scientific knowledge. Future progress in developing a functionally annotated genome map depends upon studies in model organisms, not least the mouse. Further, recent advances in genetic manipulation and in vivo, in vitro, and in silico phenotyping technologies in the mouse make annotation of the vast majority of functional elements within the mammalian genome feasible. The implementation of a Deep Genome Project—to deliver the functional biological annotation of all human orthologous genomic elements in mice—is an essential and executable strategy to transform our understanding of genetic and genomic variation in human health and disease that will catalyze delivery of the promised benefits of genomic medicine to children and adults around the world.
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- 2020
74. Mosaic KRAS mutation in a patient with encephalocraniocutaneous lipomatosis and renovascular hypertension
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Kym M. Boycott, Brian H.Y. Chung, Hussein Daoud, Lawrence Lan, Gordon K.C. Leung, Laura M McDonell, Ho Ming Luk, Stella Chim, and Janice Ip
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Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Adolescent ,Eye Diseases ,Renal Artery Obstruction ,Proto-Oncogene Mas ,Renovascular hypertension ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Lipomatosis ,Child ,Genetics (clinical) ,Base Sequence ,Mosaicism ,business.industry ,Neurocutaneous Syndromes ,medicine.disease ,Hypertension, Renovascular ,030104 developmental biology ,Child, Preschool ,030220 oncology & carcinogenesis ,Mutation ,Encephalocraniocutaneous Lipomatosis ,Tomography, X-Ray Computed ,business ,Kras mutation - Published
- 2018
75. Is PNPT1 -related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1 -related disorders
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Caitlin Goedhart, A. Micheil Innes, Alison Eaton, Oana Caluseriu, Jillian S. Parboosingh, Ryan E. Lamont, Kym M. Boycott, and Francois P. Bernier
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Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Ataxia ,Hearing loss ,Hearing Loss, Sensorineural ,Mitochondrial disease ,030105 genetics & heredity ,03 medical and health sciences ,Exome Sequencing ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,RNA, Messenger ,Cognitive decline ,Genetics (clinical) ,Exome sequencing ,Dystonia ,business.industry ,Siblings ,Middle Aged ,medicine.disease ,Pedigree ,Natural history ,Exoribonucleases ,Female ,Sensorineural hearing loss ,medicine.symptom ,business - Abstract
PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932). The latter has been described in multiple families presenting with complex neurologic manifestations in childhood. We describe adult siblings with biallelic PNPT1 variants identified through WES who presented with isolated severe congenital sensorineural hearing loss (SNHL). In their 40s, they each developed and then followed a nearly identical neurodegenerative course with ataxia, dystonia, and cognitive decline. Now in their 50s and 60s, all have developed the additional features of optic nerve atrophy, spasticity, and incontinence. The natural history of the condition in this family may suggest that the individuals previously reported as having isolated SNHL may be at risk of developing multisystem disease in late adulthood, and that PNPT1-related disorders may constitute a spectrum rather than distinct phenotypes.
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- 2018
76. When to think outside the autozygome: Best practices for exome sequencing in 'consanguineous' families
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A. Micheil Innes, Yoko Ito, Alison Eaton, Jillian S. Parboosingh, Kristin D. Kernohan, Ryan E. Lamont, Taila Hartley, Nick Barrowman, and Kym M. Boycott
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0301 basic medicine ,Male ,Canada ,Consanguinity ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,Exome Sequencing ,Genetics ,medicine ,Humans ,Exome ,Genetic Testing ,Genetics (clinical) ,Exome sequencing ,Genetic testing ,medicine.diagnostic_test ,Family structure ,Significant difference ,Homozygote ,Genetic Diseases, Inborn ,Pedigree ,030104 developmental biology ,Genetics, Population ,Mutation ,Female - Abstract
Exome sequencing (ES) is an effective diagnostic tool with a high yield in consanguineous families. However, how diagnostic yield and mode of inheritance relate to family structure has not been well delineated. We reviewed ES results from families enrolled in the Care4Rare Canada research consortium with various degrees of consanguinity. We contrasted the diagnostic yield in families with parents who are second cousins or closer ("close" consanguinity) vs those more distantly related or from isolated populations ("presumed" consanguinity). We further stratified by number of affected individuals (multiple affected ["multiplex"] vs single affected [simplex]). The overall yield in 116 families was 45.7% (n = 53) with no significant difference between subgroups. Homozygous variants accounted for 100% and 75% of diagnoses in close and presumed consanguineous multiplex families, respectively. In simplex presumed consanguineous families, a striking 46.2% of diagnoses were due to de novo variants, vs only 11.8% in simplex closely consanguineous families (88.2% homozygous). Our data underscores the high yield of ES in consanguineous families and highlights that while a singleton approach may frequently be reasonable and a responsible use of resources, trio sequencing should be strongly considered in simplex families in the absence of confirmed consanguinity given the proportion of de novo variants.
- Published
- 2019
77. MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement
- Author
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David Mowat, Sandra Donkervoort, Dimah Saade, Timothy E. Shutt, R. Hanson, Volker Straub, J.S. Parboosingh, Alessandra Carnevale, Francois P. Bernier, Pomi Yun, Rupleen Kaur, Beryl B. Cummings, I. Al Khatib, Carol J Saunders, Amy Harper, Peter I. Karachunski, Laurence Gauquelin, Leigh B. Waddell, Michelle A. Farrar, A.M. Innes, Rasha Sabouny, Asif Javed, Isabelle Thiffault, Ana Töpf, Sophelia H. S. Chan, Steven A. Moore, Katherine R. Chao, Nanna Witting, M. Leach, Jean K. Mah, C. Thompson, Rhonda E. Schnur, Joline C. Dalton, Carsten G. Bönnemann, Julia K. Goodrich, Keith A. Coffman, Prech Uapinyoying, Ryan E. Lamont, Sabine Specht, L. Medne, Grace Yoon, A. Reghan Foley, Kym M. Boycott, Payam Mohassel, John Vissing, Hilary E. Racher, Ying Hu, and M. Hainlen
- Subjects
Adult ,Male ,0301 basic medicine ,Mitochondrial DNA ,Mitochondrial Diseases ,Adolescent ,DNA Copy Number Variations ,Cell Cycle Proteins ,Disease ,Biology ,DNA, Mitochondrial ,Muscular Dystrophies ,Pathology and Forensic Medicine ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Cerebellar Diseases ,MSTO1 ,Mitochondrial fusion ,medicine ,Humans ,MtDNA depletion ,Muscular dystrophy ,Child ,Cells, Cultured ,Loss function ,Genetics ,Original Paper ,Cerebellar ataxia ,Muscles ,Fibroblasts ,Middle Aged ,medicine.disease ,Phenotype ,3. Good health ,Cytoskeletal Proteins ,030104 developmental biology ,mitochondrial fusion ,Cerebellar atrophy ,Mutation ,Female ,Neurology (clinical) ,Atrophy ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype–phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease. Electronic supplementary material The online version of this article (10.1007/s00401-019-02059-z) contains supplementary material, which is available to authorized users.
- Published
- 2019
78. A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys
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Afsana Ahmed, Aimee C. Smidt, Carol L. Clericuzio, Dennis E. Bulman, Amanda C. Smith, Sara L. Sawyer, Kym M. Boycott, David A. Dyment, Laura M McDonell, Chandree L. Beaulieu, Kristin D. Kernohan, Izabella A. Pena, and Yoko Ito
- Subjects
Male ,0301 basic medicine ,Microcephaly ,Pathology ,medicine.medical_specialty ,Genes, Recessive ,Biology ,Kidney ,medicine.disease_cause ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Missense mutation ,Abnormalities, Multiple ,Global developmental delay ,Craniofacial ,Growth Disorders ,Genetics (clinical) ,Exome sequencing ,Mutation ,Facies ,Membrane Transport Proteins ,Alopecia ,medicine.disease ,Uremia ,3. Good health ,030104 developmental biology ,Child, Preschool ,Female ,Congenital Alopecia - Abstract
A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage. Three of the children died before 3 years of age from uremia and/or sepsis. Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family. In a second family, the identical variant was shown to be heterozygous in the affected individual's parents and not homozygous in any of her unaffected siblings. ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus. Structural modeling reveals that p.Ile196Thr disrupts the hydrophobic core of ZPR1. Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase. We provide genetic and molecular evidence that a homozygous missense mutation in ZPR1 is associated with a rare and recognizable multisystem syndrome.
- Published
- 2018
79. Association of Early-Onset Spasticity and Risk for Cognitive Impairment With Mutations at Amino Acid 499 in SPAST
- Author
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Hugh J. McMillan, Meredith K. Gillespie, Kym M. Boycott, and Peter Humphreys
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Spastin ,Adolescent ,Hereditary spastic paraplegia ,Genetic counseling ,030105 genetics & heredity ,medicine.disease_cause ,Cerebral palsy ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Spastic ,Humans ,Cognitive Dysfunction ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Spasticity ,Paraplegia ,Mutation ,Spastic Paraplegia, Hereditary ,Genetic heterogeneity ,business.industry ,medicine.disease ,nervous system diseases ,Phenotype ,Muscle Spasticity ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Hereditary spastic paraplegia is a phenotypically and genetically heterogeneous group of neurodegenerative disorders characterized by lower extremity weakness and spasticity. Spastic paraplegia 4 (SPG4), caused by heterozygous mutations in the gene SPAST, typically causes a late-onset, uncomplicated form of hereditary spastic paraplegia in affected individuals. Additional clinical features in SPG4 have been reported on occasion, but no genotype-phenotype correlation has been established. Through targeted clinical testing, we identified 2 unrelated female patients with the same de novo p.Arg499His mutation in SPAST. Both patients presented with early-onset spasticity resulting in delayed motor milestones, which led to a diagnosis of cerebral palsy in one child and tethered cord in the other. Review of the literature identified several patients with mutations at amino acid 499 and early-onset symptoms associated with a risk of cognitive impairment. Early and accurate diagnosis of children with early-onset spasticity is important for informed prognosis and genetic counselling.
- Published
- 2018
80. The role of the clinician in the multi-omics era: are you ready?
- Author
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Carlos Ferreira, Tobias B. Haack, Kym M. Boycott, Saskia B. Wortmann, Carla E. M. Hollak, Mirjam Langeveld, Hans R. Waterham, Maja Tarailo-Graovac, Jiddeke M. van de Kamp, Wyeth W. Wasserman, Clara D.M. van Karnebeek, Ron A. Wevers, Ronald J.A. Wanders, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Reproduction & Development (AR&D), Laboratory Medicine, ANS - Complex Trait Genetics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Paediatric Metabolic Diseases, Endocrinology, Laboratory Genetic Metabolic Diseases, APH - Methodology, and ACS - Diabetes & metabolism
- Subjects
0301 basic medicine ,Epigenomics ,Male ,Proteomics ,Systems biology ,Big data ,Genomics ,Inherited Metabolic Disease ,Metabolomics ,Diagnosis ,Treatment ,Precision Medicine ,03 medical and health sciences ,Neonatal Screening ,All institutes and research themes of the Radboud University Medical Center ,Genetics ,Humans ,Capstone ,Inherited metabolic disease ,Patient participation ,Phenomics ,Physician's Role ,Glycomics ,Genetics (clinical) ,business.industry ,Systems Biology ,Precision medicine ,Infant, Newborn ,Omics ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Data science ,3. Good health ,Data sharing ,030104 developmental biology ,Molecular Diagnostic Techniques ,Female ,Psychology ,business - Abstract
Since Garrod’s first description of alkaptonuria in 1902, and newborn screening for phenylketonuria introduced in the 1960s, P4 medicine (preventive, predictive, personalized, and participatory) has been a reality for the clinician serving patients with inherited metabolic diseases. The era of high-throughput technologies promises to accelerate its scale dramatically. Genomics, transcriptomics, epigenomics, proteomics, glycomics, metabolomics, and lipidomics offer an amazing opportunity for holistic investigation and contextual pathophysiologic understanding of inherited metabolic diseases for precise diagnosis and tailored treatment. While each of the -omics technologies is important to systems biology, some are more mature than others. Exome sequencing is emerging as a reimbursed test in clinics around the world, and untargeted metabolomics has the potential to serve as a single biochemical testing platform. The challenge lies in the integration and cautious interpretation of these big data, with translation into clinically meaningful information and/or action for our patients. A daunting but exciting task for the clinician; we provide clinical cases to illustrate the importance of his/her role as the connector between physicians, laboratory experts and researchers in the basic, computer, and clinical sciences. Open collaborations, data sharing, functional assays, and model organisms play a key role in the validation of -omics discoveries. Having all the right expertise at the table when discussing the diagnostic approach and individualized management plan according to the information yielded by -omics investigations (e.g., actionable mutations, novel therapeutic interventions), is the stepping stone of P4 medicine. Patient participation and the adjustment of the medical team’s plan to his/her and the family’s wishes most certainly is the capstone. Are you ready?
- Published
- 2018
81. A family segregating lethal neonatal coenzyme Q(10) deficiency caused by mutations in COQ9
- Author
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Jeremy Schwartzentruber, Chandree L. Beaulieu, Karina Horsting-Wethly, Erika Aberg, Dennis E. Bulman, Yoko Ito, Lynette S. Penney, Kym M. Boycott, Jacek Majewski, Afsana Ahmed, Diana Vermunt-de Koning, Richard J. Rodenburg, and Amanda C. Smith
- Subjects
0301 basic medicine ,Coenzyme Q10 ,medicine.medical_specialty ,Genetic heterogeneity ,business.industry ,Mitochondrial disease ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Compound heterozygosity ,medicine.disease ,3. Good health ,03 medical and health sciences ,chemistry.chemical_compound ,Exon ,030104 developmental biology ,Endocrinology ,All institutes and research themes of the Radboud University Medical Center ,chemistry ,Internal medicine ,Lactic acidosis ,Genetics ,medicine ,Leigh disease ,business ,Genetics (clinical) ,Exome sequencing - Abstract
Primary CoQ10 deficiency is a clinically and genetically heterogeneous, autosomal recessive disorder resulting from mutations in genes involved in the synthesis of coenzyme Q10 (CoQ10). To date, mutations in nine proteins required for the biosynthesis of CoQ10 cause CoQ10 deficiency with varying clinical presentations. In 2009 the first patient with mutations in COQ9 was reported in an infant with a neonatal-onset, primary CoQ10 deficiency with multi-system disease. Here we describe four siblings with a previously undiagnosed lethal disorder characterized by oligohydramnios and intrauterine growth restriction, variable cardiomyopathy, anemia, and renal anomalies. The first and third pregnancy resulted in live born babies with abnormal tone who developed severe, treatment unresponsive lactic acidosis after birth and died hours later. Autopsy on one of the siblings demonstrated brain changes suggestive of the subacute necrotizing encephalopathy of Leigh disease. Whole-exome sequencing (WES) revealed the siblings shared compound heterozygous mutations in the COQ9 gene with both variants predicted to affect splicing. RT-PCR on RNA from patient fibroblasts revealed that the c.521 + 2 T > C variant resulted in splicing out of exons 4–5 and the c.711 + 3G > C variant spliced out exon 6, resulting in undetectable levels of COQ9 protein in patient fibroblasts. The biochemical profile of patient fibroblasts demonstrated a drastic reduction in CoQ10 levels. An additional peak on the chromatogram may represent accumulation of demethoxy coenzyme Q (DMQ), which was shown previously to accumulate as a result of a defect in COQ9. This family expands our understanding of this rare metabolic disease and highlights the prenatal onset, clinical variability, severity, and biochemical profile associated with COQ9-related CoQ10 deficiencies.
- Published
- 2018
82. A novel mutation in LAMC3 associated with generalized polymicrogyria of the cortex and epilepsy
- Author
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Jillian S. Parboosingh, Kym M. Boycott, M. Kerr, Jessica L. Zambonin, Elka Miller, Yanwei Xi, Sunita Venkateswaran, Taila Hartley, Ryan E. Lamont, and David A. Dyment
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0301 basic medicine ,Adolescent ,Nonsense mutation ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Epilepsy ,0302 clinical medicine ,Neurodevelopmental disorder ,Cortex (anatomy) ,Genetics ,medicine ,Polymicrogyria ,Humans ,Genetics (clinical) ,Pachygyria ,Brain ,High-Throughput Nucleotide Sequencing ,medicine.disease ,Phenotype ,Human genetics ,030104 developmental biology ,medicine.anatomical_structure ,Codon, Nonsense ,Female ,Laminin ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Occipital cortical malformation is a rare neurodevelopmental disorder characterized by pachygyria and polymicrogyria of the occipital lobes as well as global developmental delays and seizures. This condition is due to biallelic, loss-of-function mutations in LAMC3 and has been reported in four unrelated families to date. We report an individual with global delays, seizures, and polymicrogyria that extends beyond the occipital lobes and includes the frontal, parietal, temporal, and occipital lobes. Next-generation sequencing identified a homozygous nonsense mutation in LAMC3: c.3190C>T (p.Gln1064*). This finding extends the cortical phenotype associated with LAMC3 mutations.
- Published
- 2017
83. Evaluation of exome filtering techniques for the analysis of clinically relevant genes
- Author
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Taila Hartley, Najmeh Alirezaie, David A. Dyment, Peter N. Robinson, Kym M. Boycott, and Kristin D. Kernohan
- Subjects
0301 basic medicine ,In silico ,Computational Biology ,Sequence Analysis, DNA ,Computational biology ,Biology ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,Databases, Genetic ,Human Phenotype Ontology ,Genetics ,OMIM : Online Mendelian Inheritance in Man ,Humans ,Exome ,University medical ,Medical diagnosis ,Gene ,Software ,Genetics (clinical) ,Exome sequencing ,Retrospective Studies - Abstract
A significant challenge facing clinical translation of exome sequencing is meaningful and efficient variant interpretation. Each exome contains ∼500 rare coding variants; laboratories must systematically and efficiently identify which variant(s) contribute to the patient's phenotype. In silico filtering is an approach that reduces analysis time while decreasing the chances of incidental findings. We retrospectively assessed 55 solved exomes using available datasets as in silico filters: Online Mendelian Inheritance in Man (OMIM), Orphanet, Human Phenotype Ontology (HPO), and Radboudumc University Medical Center curated panels. We found that personalized panels produced using HPO terms for each patient had the highest success rate (100%), while producing considerably less variants to assess. HPO panels also captured multiple diagnoses in the same individual. We conclude that custom HPO-derived panels are an efficient and effective way to identify clinically relevant exome variants.
- Published
- 2017
84. Progress in Rare Diseases Research 2010-2016: An IRDiRC Perspective
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Ana Rath, Anneliene H. Jonker, Paul Lasko, Hugh Dawkins, Gareth Baynam, Hanns Lochmüller, Virginie Hivert, Yann Le Cam, Ruxandra Draghia-Akli, Christopher P. Austin, Lilian P.L. Lau, Christine M. Cutillo, Kym M. Boycott, and Petra Kaufmann
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,General Neuroscience ,Perspective (graphical) ,Engineering ethics ,General Medicine ,Sociology ,030105 genetics & heredity ,General Pharmacology, Toxicology and Pharmaceutics ,General Biochemistry, Genetics and Molecular Biology - Published
- 2017
85. Future of Rare Diseases Research 2017-2027: An IRDiRC Perspective
- Author
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Gareth Baynam, Carlo Incerti, Daria Julkowska, Hanns Lochmüller, Christine M. Cutillo, Ruxandra Draghia-Akli, Christopher P. Austin, Petra Kaufmann, Sharon F. Terry, Anneliene H. Jonker, Lu Wang, Lilian P.L. Lau, Béatrice de Montleau, Kym M. Boycott, Domenica Taruscio, David Thomson, Diego Ardigò, Makoto Suematsu, Hugh Dawkins, Virginie Hivert, Irene Norstedt, and Ana Rath
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,General Neuroscience ,Perspective (graphical) ,General Medicine ,Sociology ,General Pharmacology, Toxicology and Pharmaceutics ,Data science ,030217 neurology & neurosurgery ,General Biochemistry, Genetics and Molecular Biology - Published
- 2017
86. Pyridoxine-Dependent Epilepsy in Zebrafish Caused by Aldh7a1 Deficiency
- Author
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Vishal Saxena, Nathalie Lepage, Marc Ekker, Kate Daniel, Alex MacKenzie, Izabella A. Pena, Pranesh Chakraborty, David A. Dyment, Kym M. Boycott, Devon L. Johnstone, Hellen Weinschutz Mendes, Yann Roussel, Marjolein Bosma, Tuan V. Bui, Clara D.M. van Karnebeek, Kevin Mongeon, Nanda M. Verhoeven-Duif, ANS - Cellular & Molecular Mechanisms, and Other departments
- Subjects
Developmental and Behavioral Genetics ,0301 basic medicine ,Pathogenesis ,Gene Knockout Techniques ,chemistry.chemical_compound ,Epilepsy ,0302 clinical medicine ,heterocyclic compounds ,Pyridoxine-dependent epilepsy ,Zebrafish ,gamma-Aminobutyric Acid ,education.field_of_study ,aldh7a1 ,Pyridoxine ,3. Good health ,medicine.drug ,medicine.medical_specialty ,animal structures ,Population ,macromolecular substances ,Investigations ,Biology ,gamma-Aminobutyric acid ,03 medical and health sciences ,Seizures ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,education ,Pyridoxal ,Lysine ,fungi ,lysine metabolism ,pyridoxine-dependent epilepsy ,Aldehyde Dehydrogenase ,medicine.disease ,biology.organism_classification ,Vitamin B 6 ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,Mutation ,metabolic epilepsy ,sense organs ,zebrafish model ,030217 neurology & neurosurgery - Abstract
Pyridoxine-dependent epilepsy (PDE) is a severe neonatal seizure disorder and is here modeled in aldh7a1 -/- zebrafish. Mutant larvae display spontaneous.., Pyridoxine-dependent epilepsy (PDE) is a rare disease characterized by mutations in the lysine degradation gene ALDH7A1 leading to recurrent neonatal seizures, which are uniquely alleviated by high doses of pyridoxine or pyridoxal 5′-phosphate (vitamin B6 vitamers). Despite treatment, neurodevelopmental disabilities are still observed in most PDE patients underlining the need for adjunct therapies. Over 60 years after the initial description of PDE, we report the first animal model for this disease: an aldh7a1-null zebrafish (Danio rerio) displaying deficient lysine metabolism and spontaneous and recurrent seizures in the larval stage (10 days postfertilization). Epileptiform electrographic activity was observed uniquely in mutants as a series of population bursts in tectal recordings. Remarkably, as is the case in human PDE, the seizures show an almost immediate sensitivity to pyridoxine and pyridoxal 5′-phosphate, with a resulting extension of the life span. Lysine supplementation aggravates the phenotype, inducing earlier seizure onset and death. By using mass spectrometry techniques, we further explored the metabolic effect of aldh7a1 knockout. Impaired lysine degradation with accumulation of PDE biomarkers, B6 deficiency, and low γ-aminobutyric acid levels were observed in the aldh7a1−/− larvae, which may play a significant role in the seizure phenotype and PDE pathogenesis. This novel model provides valuable insights into PDE pathophysiology; further research may offer new opportunities for drug discovery to control seizure activity and improve neurodevelopmental outcomes for PDE.
- Published
- 2017
87. 'Matching' consent to purpose: The example of the Matchmaker Exchange
- Author
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Heidi L. Rehm, Matthew E. Hurles, Stephanie O.M. Dyke, Bartha Maria Knoppers, Kym M. Boycott, Michael Brudno, Ada Hamosh, Anthony A. Philippakis, and Helen V. Firth
- Subjects
0301 basic medicine ,Matching (statistics) ,Candidate gene ,business.industry ,Internet privacy ,Information Dissemination ,Biology ,Precision medicine ,Odds ,Data sharing ,03 medical and health sciences ,030104 developmental biology ,Data access ,Genetics ,Personalized medicine ,business ,Genetics (clinical) - Abstract
The Matchmaker Exchange (MME) connects rare disease clinicians and researchers to facilitate the sharing of data from undiagnosed patients for the purpose of novel gene discovery. Such sharing raises the odds that two or more similar patients with candidate genes in common may be found, thereby allowing their condition to be more readily studied and understood. Consent considerations for data sharing in MME included both the ethical and legal differences between clinical and research settings and the level of privacy risk involved in sharing varying amounts of rare disease patient data to enable patient matches. In this commentary, we discuss these consent considerations and the resulting MME Consent Policy as they may be relevant to other international data sharing initiatives.
- Published
- 2017
88. Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome
- Author
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S. Ordorica, E. Creede, David A. Dyment, Kym M. Boycott, L. Gallagher, D. Lahey, P. Y B Au, K. Mina, Stephanie Broley, Gareth Baynam, and L. Huang
- Subjects
0301 basic medicine ,Genetics ,Pediatrics ,medicine.medical_specialty ,Polydactyly ,General Medicine ,Scoliosis ,Biology ,medicine.disease ,Frameshift mutation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Anal atresia ,Intellectual disability ,medicine ,Etiology ,Haploinsufficiency ,030217 neurology & neurosurgery ,Genetics (clinical) ,Chromosomal inversion - Abstract
The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5′UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.
- Published
- 2017
89. Benchmarking outcomes in the Neonatal Intensive Care Unit: Cytogenetic and molecular diagnostic rates in a retrospective cohort
- Author
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Christine M. Armour, Meredith K. Gillespie, Faheem Malam, Julie Richer, Kym M. Boycott, Sarah L. Sawyer, Erika Bariciak, Sarah M. Nikkel, Taila Hartley, David A. Dyment, and Gail E. Graham
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pediatrics ,Neonatal intensive care unit ,business.industry ,Genetic heterogeneity ,Retrospective cohort study ,Disease ,030105 genetics & heredity ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Genetics ,medicine ,Medical genetics ,Medical diagnosis ,Differential diagnosis ,business ,Genetics (clinical) ,Exome sequencing - Abstract
Genetic disease and congenital anomalies continue to be a leading cause of neonate mortality and morbidity. A genetic diagnosis in the neonatal intensive care unit (NICU) can be a challenge given the associated genetic heterogeneity and early stage of a disease. We set out to evaluate the outcomes of Medical Genetics consultation in the NICU in terms of cytogenetic and molecular diagnostic rates and impact on management. We retrospectively reviewed 132 charts from patients admitted to the NICU who received a Medical Genetics diagnostic evaluation over a 2 year period. Of the 132 patients reviewed, 26% (34/132) received a cytogenetic or molecular diagnosis based on the Medical Genetics diagnostic evaluation; only 10% (13/132) received a diagnosis during their admission. The additional 16% (21 patients) received their diagnosis following NICU discharge, but based on a genetic test initiated during hospital-stay. Mean time from NICU admission to confirmed diagnosis was 24 days. For those who received a genetic diagnosis, the information was considered beneficial for clinical management in all, and a direct change to medical management occurred for 12% (4/32). For those non-diagnosed infants seen in out-patient follow-up clinic, diagnoses were made in 8% (3/37). The diagnoses made post-discharge from the NICU comprised a greater number of Mendelian disorders and represent an opportunity to improve genetic care. The adoption of diagnostic tools, such as exome sequencing, used in parallel with traditional approaches will improve rate of diagnoses and will have a significant impact, in particular when the differential diagnosis is broad.
- Published
- 2017
90. Whole-transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy
- Author
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Kristin D. Kernohan, Laure Frésard, Zachary Zappala, Taila Hartley, Kevin S. Smith, Justin Wagner, Hongbin Xu, Arran McBride, Pierre R. Bourque, CareRare Canada Consortium, Steffany A. L. Bennett, David A. Dyment, Kym M. Boycott, Stephen B. Montgomery, and Jodi Warman Chardon
- Subjects
0301 basic medicine ,Mutation ,In silico ,RNA ,Spinal muscular atrophy ,Biology ,medicine.disease ,medicine.disease_cause ,Bioinformatics ,DNA sequencing ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,Spinal muscular atrophy with progressive myoclonic epilepsy ,RNA splicing ,Genetics ,ASAH1 ,medicine ,Genetics (clinical) - Abstract
At least 15% of the disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in noncoding regions. Whole-transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease-relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p C;p.Lys168Asn) and provided a molecular diagnosis of autosomal-recessive spinal muscular atrophy with progressive myoclonic epilepsy. Our findings demonstrate the utility of RNA sequencing from blood to identify splice-impacting disease mutations for nonhematological conditions, providing a diagnosis for these otherwise unsolved patients.
- Published
- 2017
91. Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing
- Author
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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
- Subjects
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.
- Published
- 2017
92. Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy
- Author
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Taila Hartley, Thi-Tuyet-Mai Nguyen, Jacek Majewski, Anik St-Denis, Philippe M. Campeau, David A. Dyment, Taroh Kinoshita, Françoise Le Deist, Devon L. Johnstone, Yoshiko Murakami, Asif Doja, Claire Goldsmith, Martine Tétreault, Justin D. Wagner, Kym M. Boycott, Kristin D. Kernohan, Dennis E. Bulman, and Lijia Huang
- Subjects
Adult ,0301 basic medicine ,Glycosylation ,Glycosylphosphatidylinositols ,Developmental Disabilities ,Protein subunit ,Hemoglobinuria, Paroxysmal ,Compound heterozygosity ,Immunoglobulin D ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Seizures ,Intellectual Disability ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Global developmental delay ,Child ,Molecular Biology ,Gene ,Genetics (clinical) ,biology ,Membrane Proteins ,General Medicine ,Phenotype ,Hypotonia ,Pedigree ,030104 developmental biology ,Hexosyltransferases ,chemistry ,Mutation ,biology.protein ,Muscle Hypotonia ,medicine.symptom ,Spasms, Infantile - Abstract
There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability. Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis. Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes. Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development.
- Published
- 2017
93. Expansion of the <scp>GLE1</scp> ‐associated arthrogryposis multiplex congenita clinical spectrum
- Author
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Jillian S. Parboosingh, Kym M. Boycott, Carsten G. Bönnemann, A. Micheil Innes, Christopher Smith, Jean K. Mah, Francois P. Bernier, and Ryan E. Lamont
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Male ,musculoskeletal diseases ,0301 basic medicine ,Nucleocytoplasmic Transport Proteins ,Neuromuscular disease ,Genotype ,RNA Splicing ,Population ,Biology ,Compound heterozygosity ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Child ,education ,Exome ,Finland ,Genetics (clinical) ,Arthrogryposis ,Gastrostomy ,education.field_of_study ,Arthrogryposis multiplex congenita ,Lethal congenital contracture syndrome ,Infant, Newborn ,Spinal muscular atrophy ,medicine.disease ,Pedigree ,3. Good health ,030104 developmental biology ,Mutation ,medicine.symptom - Abstract
Mutations in GLE1 cause two recessive subtypes of arthrogryposis multiplex congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period. GLE1 related AMC has been almost exclusively reported in the Finnish population and is caused by a relatively common pathogenic splicing mutation in that population. Here, we report two non-Finnish brothers with novel compound heterozygous splicing mutations in GLE1, one of whom has survived to 12 years of age. We also demonstrate low levels of residual wild type transcript in fibroblasts from the surviving brother, suggesting that this residual wild-type transcript may contribute to the relatively longer-term survival in this family. We provide a detailed clinical report on the surviving patient, providing the first insight into the natural history of this rare neuromuscular disease. We also suggest that lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn disease (LAAHD), the two AMC subtypes related to GLE1, do not have sufficient clinical or molecular differentiation to be considered allelic disorders. Rather, GLE1 mutations cause a variable spectrum of AMC severity including a non-lethal variant described herein.
- Published
- 2017
94. Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly
- Author
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Jeremy Schwartzentruber, Jacek Majewski, Susan Blaser, Nicole Martin, David Chitayat, Yanwei Xi, Arran McBride, Kym M. Boycott, Kristin D. Kernohan, and David A. Dyment
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0301 basic medicine ,Genetics ,Microcephaly ,Methyltransferase ,030102 biochemistry & molecular biology ,Arginine ,Lysine ,Brachydactyly ,Methylation ,Biology ,medicine.disease ,Null allele ,03 medical and health sciences ,030104 developmental biology ,Histone ,medicine ,biology.protein ,Genetics (clinical) - Abstract
Post-translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition.
- Published
- 2016
95. The Human Phenotype Ontology in 2017
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Rachel Thompson, Stanley J. F. Laulederkind, Richard H. Scott, Panagiotis I. Sergouniotis, Ada Hamosh, Mark Engelstad, Hanns Lochmüller, Gareth Baynam, Richard Sever, Roger James, Hugh Dawkins, Laureen E. Connell, C. Turner, Andrew D. Devereau, Susan M. Bello, Michael Brudno, Courtney Hum, Cynthia L. Smith, Julie A. McMurry, Michael M. Segal, Damian Smedley, Gholson J. Lyon, Helen V. Firth, Ingo Helbig, Tom Vulliamy, Roland Krause, Patrick F. Chinnery, Franz Schaefer, Ernest Turro, Melissa A. Haendel, Cornelius F. Boerkoel, Peter N. Robinson, Willem H. Ouwehand, Orion J. Buske, Kym M. Boycott, Volker Straub, Bert B.A. de Vries, Daniel Greene, Valentina Cipriani, Erin D. Foster, Annie Olry, Julius O.B. Jacobsen, Laura E. DeMare, Marijcke W. M. Veltman, Nikolas Pontikos, Andreas Zankl, Tudor Groza, Kathleen Freson, Sebastian Köhler, Ana Rath, Nicole Vasilevsky, Julie von Ziegenweidt, Ségolène Aymé, Soichi Ogishima, Johanna A. Jähn, Jing Yu, Tomasz Zemojtel, Stephan Züchner, and Christopher J. Mungall
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0301 basic medicine ,Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine] ,Genomics ,Translational research ,Computational biology ,Biology ,Ontology (information science) ,Terminology ,Translational Research, Biomedical ,03 medical and health sciences ,Rare Diseases ,Human Phenotype Ontology ,Genetics ,Database Issue ,Humans ,Precision Medicine ,Multidisciplinary, general & others [D99] [Human health sciences] ,Genetic Association Studies ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Computational Biology ,Biological Ontologies ,Precision medicine ,Phenotype ,3. Good health ,030104 developmental biology ,Algorithms ,Software - Abstract
Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology. ispartof: Nucleic Acids Research vol:45 issue:D1 pages:D865-D876 ispartof: location:England status: published
- Published
- 2016
96. Implementation of Epilepsy Multigene Panel Testing in Ontario, Canada
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O. Carter Snead, David A. Dyment, Grace U Ediae, Lysa Boissé Lomax, Katherine Muir, Taila Hartley, Asuri N. Prasad, Murray A. Potter, Bekim Sadikovic, Dimitri J. Stavropoulos, Kym M. Boycott, Ayman Hassan, and Olga Jarinova
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medicine.medical_specialty ,Service (systems architecture) ,Epilepsy ,medicine.diagnostic_test ,business.industry ,Genetic heterogeneity ,General Medicine ,Gene panel sequencing ,medicine.disease ,Test (assessment) ,Neurology ,Family medicine ,Implementation ,Health care ,Genetic predisposition ,Next-generation sequencing ,Medicine ,Neurology (clinical) ,business ,Genetic testing ,Ontario canada - Abstract
Epilepsy is a common neurological condition that shows a marked genetic predisposition. The advent of next-generation sequencing (NGS) has transformed clinical genetic testing by allowing the rapid screen for causative variants in multiple genes. There are currently no NGS-based multigene panel diagnostic tests available for epilepsy as a licensed clinical diagnostic test in Ontario, Canada. Eligible patient samples are sent out of country for testing by commercial laboratories, which incurs significant cost to the public healthcare system.An expert Working Group of medical geneticists, pediatric neurologists/epileptologists, biochemical geneticists, and clinical molecular geneticists from Ontario was formed by the Laboratories and Genetics Branch of the Ontario Ministry of Health and Long-Term Care to develop a programmatic approach to implementing epilepsy panel testing as a provincial service.The Working Group made several recommendations for testing to support the clinical delivery of care in Ontario. First, an extension of community healthcare outcomes-based program should be incorporated to inform and educate ordering providers when requesting and interpreting a genetic panel test. Second, any gene panel testing must be "evidence-based" and takes into account varied clinical indications to reduce the chance of uncertain and secondary results. Finally, an ongoing evaluative process was recommended to ensure continued test improvement for the future.This epilepsy panel testing implementation plan will be a model for genetic care directed toward a specific set of conditions in the province and serve as a prototype for genetic testing for other genetically heterogeneous diseases.Mise en œuvre d’un test diagnostique permettant en Ontario l’analyse d’un panel de plusieurs gènes liés à l’épilepsie.Contexte:L’épilepsie demeure un trouble neurologique fréquent dont la prédisposition génétique apparaît notable. L’émergence du séquençage de nouvelle génération (SNG) a aussi transformé les tests génétiques en permettant un dépistage rapide des variantes causales que l’on retrouve dans de nombreux gènes. À l’heure actuelle, il n’existe pas, pour l’épilepsie, de tests diagnostiques homologués qui permettent en Ontario l’analyse d’un panel de gènes en vertu du SNG. Les échantillons de patients admissibles sont alors envoyés à l’extérieur du Canada afin d’être analysés par des laboratoires commerciaux, ce qui pèse lourd dans les budgets des systèmes publics de santé. Objectif : Un groupe de travail formé d’experts (généticiens médicaux, neurologues pédiatriques et spécialistes en épileptologie, généticiens biochimiques et généticiens moléculaires cliniques) a été formé par le service des laboratoires et de la génétique des ministères de la Santé et des Soins de Longue durée de l’Ontario afin d’élaborer une démarche programmatique visant à mettre en œuvre des tests diagnostiques basés sur un panel de plusieurs gènes. Ces tests seraient ensuite reconnus à titre de service public. Résultats:En matière de dépistage, ce groupe de travail a ainsi émis plusieurs recommandations visant à accompagner la prestation clinique en Ontario. Tout d’abord, un programme s’inspirant du projet « ECHO » (Extension of Community Healthcare Outcomes) devrait être ajouté dans le but de renseigner et de sensibiliser les prestataires de soins de santé qui demandent et qui interprètent ces tests basés sur un panel de plusieurs gènes. Ensuite, tout test de ce type doit reposer sur des preuves et tenir compte d’une panoplie d’indications cliniques afin de réduire les possibilités d’incertitude et de résultats secondaires. Enfin, il a été recommandé de procéder à un processus continu d’évaluation pour s’assurer que ces tests puissent être améliorés dans le futur. Conclusion:Ce plan de mise en œuvre de tests basés sur un panel de plusieurs gènes deviendra un modèle pour les soins destinés à un ensemble spécifique de problèmes de santé en Ontario. Outre l’épilepsie, il pourra servir comme prototype pour le dépistage d’autres maladies hétérogènes sur le plan génétique.
- Published
- 2019
97. Phenotype delineation of ZNF462 related syndrome
- Author
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Sarah Savage, Maximilian Muenke, Kym M. Boycott, Lynn Pais, Koen L.I. van Gassen, Julian A. Martinez-Agosto, Jacques C. Giltay, Eleina M. England, Oliver Bell, Stephanie Blaney, Nicole Fleischer, Maria Iascone, Pedro A. Sanchez-Lara, Sarah E. Mazzola, Tiong Yang Tan, Elizabeth C. Engle, Tommy Hu, Maria Francesca Bedeschi, Brenda J. Barry, Rebecca Signer, Marie-Ange Delrue, Sung-Kook Hong, Wilfredo Torres-Martinez, Esther Kinning, Charlotte W. Ockeloen, Elaine H. Zackai, Benjamin Cogné, Darius J. Adams, Betrand Isidor, Paul Kruszka, Julie Jurgens, and Kayla Treat
- Subjects
Adult ,Male ,Adolescent ,autism spectrum disorders ,Nerve Tissue Proteins ,Bioinformatics ,Article ,Craniosynostosis ,corpus callosum ,Dysgenesis ,ptosis ,Genetics ,Humans ,Medicine ,Genetics(clinical) ,Child ,Genetics (clinical) ,Loss function ,business.industry ,Facies ,Infant ,Syndrome ,medicine.disease ,Hypotonia ,DNA-Binding Proteins ,ZNF462 ,developmental delay ,craniosynostosis ,Phenotype ,Palpebral fissure ,Autism spectrum disorder ,Child, Preschool ,Noonan syndrome ,Female ,medicine.symptom ,business ,Haploinsufficiency ,Transcription Factors ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 208539.pdf (Publisher’s version ) (Closed access) Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.
- Published
- 2019
98. p21 protein-activated kinase 1 is associated with severe regressive autism, and epilepsy
- Author
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Kristin D. Kernohan, Samantha K Rojas, Taila Hartley, Kym M. Boycott, David A. Dyment, Sarah Dyack, and Arran McBride
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Adolescent ,GTPase ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,PAK1 ,GTP-Binding Proteins ,Intellectual Disability ,Exome Sequencing ,Genetics ,Humans ,Genetic Predisposition to Disease ,Autistic Disorder ,Phosphorylation ,p21-activated kinases ,Child ,Genetics (clinical) ,Exome sequencing ,Genetic Association Studies ,Epilepsy ,Kinase ,Wnt signaling pathway ,Regressive autism ,030104 developmental biology ,p21-Activated Kinases ,Child, Preschool ,Cancer research ,Female ,Signal Transduction - Abstract
The p21-activated kinase (PAK) family of proteins function as key effectors of RHO family GTPases in mammalian cells to regulate many pathways including Ras/Raf/MEK/ERK and Wnt/β-catenin, amongst others. Here we report an individual with a novel autosomal dominant disorder characterized by severe regressive autism, intellectual disability, and epilepsy. Exome sequencing of the proband and her parents revealed a de novo variant in the PAK1 gene ([NM_001128620] c.362C>T/p.Pro121Leu). Studies in patient cells showed a clear effect on PAK1 protein function, including altered phosphorylation of targets (JNK and ERK), decreased abundance of β-catenin, and concomitant altered expression downstream of these key regulators. Our findings add PAK1 to the list of PAK proteins and kinases which when mutated cause rare genetic diseases.
- Published
- 2019
99. International collaborative actions and transparency to understand, diagnose, and develop therapies for rare diseases
- Author
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Christine M. Cutillo, Kym M. Boycott, Lilian P.L. Lau, and Christopher P. Austin
- Subjects
0301 basic medicine ,Open science ,Orphan Drug Production ,International Cooperation ,MEDLINE ,Information Dissemination ,Patient advocacy ,03 medical and health sciences ,0302 clinical medicine ,Rare Diseases ,Inventions ,Stakeholder Participation ,Research Support as Topic ,Humans ,Biomarkers & Diagnostic Imaging ,business.industry ,Public relations ,Transparency (behavior) ,Social Control, Formal ,030104 developmental biology ,Knowledge ,Commentary ,Molecular Medicine ,Personalized medicine ,Genetics, Gene Therapy & Genetic Disease ,business ,030217 neurology & neurosurgery ,Social control ,Rare disease - Abstract
Rare diseases, which affect over 350 million people worldwide and frequently go undiagnosed or misdiagnosed for years, suffer from sparse and dispersed medical knowledge leading to even rarer approved and effective therapeutic options for patients. A vast, unmet need for research and investment to advance diagnostic capabilities and therapeutic development must be confronted, despite the myriad of challenges faced. Several fundamental shifts are changing the landscape of rare diseases research and development, particularly with the application and extension of results to common diseases and the advancement of personalized medicine initiatives. Collaborative strategies that pool resources and knowledge are vital, including team science, research networks, novel funding models, shared knowledge platforms, and innovative regulatory frameworks. Importantly, patients are also increasingly involved as research partners and funders, pushing for open science and transparency, and breaking down data silos and geographical borders, often enabled by online platforms accessible from across the globe. The International Rare Diseases Research Consortium (IRDiRC), established in 2011, has been working diligently to unify stakeholders (e.g., funding bodies, companies, umbrella patient advocacy groups, researchers, and experts) to seek and drive solutions that aim to accelerate diagnosis and therapeutic development for rare diseases worldwide. Further and future advances will depend on continued collaborations and cooperation among stakeholders, working hand in hand with patients, and exponentially improving research and development efficiency. Critically, engagement with stakeholders from underrepresented populations and less‐developed countries must be prioritized, to enable all people living with a rare disease to receive an accurate diagnosis, care, and therapy.
- Published
- 2019
100. A diagnosis for all rare genetic diseases: the horizon and the next frontiers
- Author
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I. Karen Temple, Richard A. Gibbs, Taila Hartley, Axel Visel, John W Belmont, Olaf Riess, Deborah J G Mackay, A. Micheil Innes, Sally L. Dunwoodie, Timo Lassmann, Nebojsa Jojic, Leslie G. Biesecker, Kym M. Boycott, and Gareth Baynam
- Subjects
media_common.quotation_subject ,Biology ,Medical and Health Sciences ,Whole Exome Sequencing ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,Translational Research, Biomedical ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Optimism ,Leverage (negotiation) ,law ,Exome Sequencing ,Humans ,Exome ,Genetic Testing ,Clinical care ,Translational Medical Research ,Exome sequencing ,030304 developmental biology ,media_common ,0303 health sciences ,Genome ,Genome, Human ,High-Throughput Nucleotide Sequencing ,DNA ,Sequence Analysis, DNA ,Biological Sciences ,Data science ,3. Good health ,CLARITY ,Sequence Analysis ,030217 neurology & neurosurgery ,Human ,Developmental Biology ,Rare disease - Abstract
The introduction of exome sequencing in the clinic has sparked tremendous optimism for the future of rare disease diagnosis, and there is exciting opportunity to further leverage these advances. To provide diagnostic clarity to all of these patients, however, there is a critical need for the field to develop and implement strategies to understand the mechanisms underlying all rare diseases and translate these to clinical care.
- Published
- 2019
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