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1. The phenotypic spectrum and genotype-phenotype correlations in 106 patients with variants in major autism gene CHD8

Author

Alexander J. M. Dingemans, Kim M. G. Truijen, Sam van de Ven, Raphael Bernier, Ernie M. H. F. Bongers, Arjan Bouman, Laura de Graaff – Herder, Evan E. Eichler, Erica H. Gerkes, Christa M. De Geus, Johanna M. van Hagen, Philip R. Jansen, Jennifer Kerkhof, Anneke J. A. Kievit, Tjitske Kleefstra, Saskia M. Maas, Stella A. de Man, Haley McConkey, Wesley G. Patterson, Amy T. Dobson, Eloise J. Prijoles, Bekim Sadikovic, Raissa Relator, Roger E. Stevenson, Connie T. R. M. Stumpel, Malou Heijligers, Kyra E. Stuurman, Katharina Löhner, Shimriet Zeidler, Jennifer A. Lee, Amanda Lindy, Fanggeng Zou, Matthew L. Tedder, Lisenka E. L. M. Vissers, and Bert B. A. de Vries

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies have shown that intellectual developmental disorder with autism and macrocephaly (IDDAM), the syndrome caused by pathogenic variants in CHD8, consists of a broad range of phenotypic abnormalities. We collected and reviewed 106 individuals with IDDAM, including 36 individuals not previously published, thus enabling thorough genotype–phenotype analyses, involving the CHD8 mutation spectrum, characterization of the CHD8 DNA methylation episignature, and the systematic analysis of phenotypes collected in Human Phenotype Ontology (HPO). We identified 29 unique nonsense, 25 frameshift, 24 missense, and 12 splice site variants. Furthermore, two unique inframe deletions, one larger deletion (exons 26–28), and one translocation were observed. Methylation analysis was performed for 13 patients, 11 of which showed the previously established episignature for IDDAM (85%) associated with CHD8 haploinsufficiency, one analysis was inconclusive, and one showing a possible gain-of-function signature instead of the expected haploinsufficiency signature was observed. Consistent with previous studies, phenotypical abnormalities affected multiple organ systems. Many neurological abnormalities, like intellectual disability (68%) and hypotonia (29%) were observed, as well as a wide variety of behavioural abnormalities (88%). Most frequently observed behavioural problems included autism spectrum disorder (76%), short attention span (32%), abnormal social behaviour (31%), sleep disturbance (29%) and impaired social interactions (28%). Furthermore, abnormalities in the digestive (53%), musculoskeletal (79%) and genitourinary systems (18%) were noted. Although no significant difference in severity was observed between males and females, individuals with a missense variant were less severely affected. Our study provides an extensive review of all phenotypic abnormalities in patients with IDDAM and provides clinical recommendations, which will be of significant value to individuals with a pathogenic variant in CHD8, their families, and clinicians as it gives a more refined insight into the clinical and molecular spectrum of IDDAM, which is essential for accurate care and counselling.

Published
2022
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2. The Autism Biomarkers Consortium for Clinical Trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials

Author

Frederick Shic, Adam J. Naples, Erin C. Barney, Shou An Chang, Beibin Li, Takumi McAllister, Minah Kim, Kelsey J. Dommer, Simone Hasselmo, Adham Atyabi, Quan Wang, Gerhard Helleman, April R. Levin, Helen Seow, Raphael Bernier, Katarzyna Charwaska, Geraldine Dawson, James Dziura, Susan Faja, Shafali Spurling Jeste, Scott P. Johnson, Michael Murias, Charles A. Nelson, Maura Sabatos-DeVito, Damla Senturk, Catherine A. Sugar, Sara J. Webb, and James C. McPartland

Subjects
Autism spectrum disorder, Biomarkers, Eye tracking, Visual attention, Face processing, Biological motion, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Eye tracking (ET) is a powerful methodology for studying attentional processes through quantification of eye movements. The precision, usability, and cost-effectiveness of ET render it a promising platform for developing biomarkers for use in clinical trials for autism spectrum disorder (ASD). Methods The Autism Biomarkers Consortium for Clinical Trials conducted a multisite, observational study of 6–11-year-old children with ASD (n = 280) and typical development (TD, n = 119). The ET battery included: Activity Monitoring, Social Interactive, Static Social Scenes, Biological Motion Preference, and Pupillary Light Reflex tasks. A priori, gaze to faces in Activity Monitoring, Social Interactive, and Static Social Scenes tasks were aggregated into an Oculomotor Index of Gaze to Human Faces (OMI) as the primary outcome measure. This work reports on fundamental biomarker properties (data acquisition rates, construct validity, six-week stability, group discrimination, and clinical relationships) derived from these assays that serve as a base for subsequent development of clinical trial biomarker applications. Results All tasks exhibited excellent acquisition rates, met expectations for construct validity, had moderate or high six-week stabilities, and highlighted subsets of the ASD group with distinct biomarker performance. Within ASD, higher OMI was associated with increased memory for faces, decreased autism symptom severity, and higher verbal IQ and pragmatic communication skills. Limitations No specific interventions were administered in this study, limiting information about how ET biomarkers track or predict outcomes in response to treatment. This study did not consider co-occurrence of psychiatric conditions nor specificity in comparison with non-ASD special populations, therefore limiting our understanding of the applicability of outcomes to specific clinical contexts-of-use. Research-grade protocols and equipment were used; further studies are needed to explore deployment in less standardized contexts. Conclusions All ET tasks met expectations regarding biomarker properties, with strongest performance for tasks associated with attention to human faces and weakest performance associated with biological motion preference. Based on these data, the OMI has been accepted to the FDA’s Biomarker Qualification program, providing a path for advancing efforts to develop biomarkers for use in clinical trials.

Published
2022
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3. Resting state EEG in youth with ASD: age, sex, and relation to phenotype

Author

Emily Neuhaus, Sarah J. Lowry, Megha Santhosh, Anna Kresse, Laura A. Edwards, Jack Keller, Erin J. Libsack, Veronica Y. Kang, Adam Naples, Allison Jack, Shafali Jeste, James C. McPartland, Elizabeth Aylward, Raphael Bernier, Susan Bookheimer, Mirella Dapretto, John D. Van Horn, Kevin Pelphrey, Sara Jane Webb, and and the ACE GENDAAR Network

Subjects
Autism, Biomarker, EEG, Electroencephalography, Resting, Alpha, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Background Identification of ASD biomarkers is a key priority for understanding etiology, facilitating early diagnosis, monitoring developmental trajectories, and targeting treatment efforts. Efforts have included exploration of resting state encephalography (EEG), which has a variety of relevant neurodevelopmental correlates and can be collected with minimal burden. However, EEG biomarkers may not be equally valid across the autism spectrum, as ASD is strikingly heterogeneous and individual differences may moderate EEG-behavior associations. Biological sex is a particularly important potential moderator, as females with ASD appear to differ from males with ASD in important ways that may influence biomarker accuracy. Methods We examined effects of biological sex, age, and ASD diagnosis on resting state EEG among a large, sex-balanced sample of youth with (N = 142, 43% female) and without (N = 138, 49% female) ASD collected across four research sites. Absolute power was extracted across five frequency bands and nine brain regions, and effects of sex, age, and diagnosis were analyzed using mixed-effects linear regression models. Exploratory partial correlations were computed to examine EEG-behavior associations in ASD, with emphasis on possible sex differences in associations. Results Decreased EEG power across multiple frequencies was associated with female sex and older age. Youth with ASD displayed decreased alpha power relative to peers without ASD, suggesting increased neural activation during rest. Associations between EEG and behavior varied by sex. Whereas power across various frequencies correlated with social skills, nonverbal IQ, and repetitive behavior for males with ASD, no such associations were observed for females with ASD. Conclusions Research using EEG as a possible ASD biomarker must consider individual differences among participants, as these features influence baseline EEG measures and moderate associations between EEG and important behavioral outcomes. Failure to consider factors such as biological sex in such research risks defining biomarkers that misrepresent females with ASD, hindering understanding of the neurobiology, development, and intervention response of this important population.

Published
2021
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4. Expert Clinician Certainty in Diagnosing Autism Spectrum Disorder in 16-30-Month-Olds: A Multi-Site Trial Secondary Analysis

Author

Cheryl Klaiman, Stormi White, Shana Richardson, Emma McQueen, Hasse Walum, Christa Aoki, Christopher Smith, Mendy Minjarez, Raphael Bernier, Ernest Pedapati, Somer Bishop, Whitney Ence, Allison Wainer, Jennifer Moriuchi, Sew-Wah Tay, Yiming Deng, Warren Jones, Scott Gillespie, and Ami Klin

Abstract

Differential diagnosis of young children with suspected autism spectrum disorder (ASD) is challenging, and clinician uncertainty about a child's diagnosis may contribute to misdiagnosis and subsequent delays in access to early treatment. The current study was designed to replicate and expand a recent report in this Journal (McDonnell et al. in "J Autism Dev Disord," v49:1391-1401, https://doi.org/10.1080/15374416.2020.1823850, 2019), in which only 60% of diagnoses were made with complete certainty by clinicians evaluating 478 toddlers and preschool children referred for possible ASD to specialized clinics. In this study, secondary analyses were performed on diagnostic, demographic and clinical data for 496 16-30-month-old children who were consecutive referrals to a 6-site clinical trial executed by specialized centers with experienced clinicians following best-practice procedures for the diagnosis of ASD. Overall, 70.2% of diagnoses were made with complete certainty. The most important factor associated with clinician uncertainty was mid-level autism-related symptomatology. Mid-level verbal age equivalents were also associated with clinician uncertainty, but measures of symptomatology were stronger predictors. None of the socio-demographic variables, including sex of the child, was significantly associated with clinician certainty. Close to one third of early diagnoses of ASD are made with a degree of uncertainty. The delineation of specific ranges on the ADOS-2 most likely to result in clinician uncertainty identified in this study may provide an opportunity to reduce random subjectivity in diagnostic decision-making via calibration of young-child diagnostic thresholds based on later-age longitudinal diagnostic outcome data, and via standardization of decision-making in regard to clinical scenarios frequently encountered by clinicians.

Published
2024
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5. Relative burden of large CNVs on a range of neurodevelopmental phenotypes.

Author

Santhosh Girirajan, Zoran Brkanac, Bradley P Coe, Carl Baker, Laura Vives, Tiffany H Vu, Neil Shafer, Raphael Bernier, Giovanni B Ferrero, Margherita Silengo, Stephen T Warren, Carlos S Moreno, Marco Fichera, Corrado Romano, Wendy H Raskind, and Evan E Eichler

Subjects
Genetics, QH426-470
Abstract

While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID-associated phenotypes compared to autism (p = 9.58 × 10(-11), odds ratio = 4.59), dyslexia (p = 3.81 × 10(-18), odds ratio = 14.45), or controls (p = 2.75 × 10(-17), odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4 × 10(-6), odds ratio = 6) or ID (16%, p = 3.55 × 10(-12), odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).

Published
2011
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6. Long-term real-life outcomes of the Clareon® hydrophobic intraocular lens: the Clarte study in 191 eyes

Author

Hugo Bouvarel, Emilie Agard, Jérémy Billant, Antoine Levron, Roman Chudzinski, Hélène Plas, Raphaël Bernier, Lucas Sejournet, Mayeul Chaperon, and Corinne Dot

Subjects
Cataract surgery, Intraocular lens, Visual acuity, Capsule opacification, Ophthalmology, RE1-994
Abstract

Abstract Background To describe and analyze the real-life refractive, functional and safety outcomes of the Clareon® intraocular lens (IOL) after 3 years. Methods Data was collected retrospectively for observational purposes between July 2017 and December 2019 in the ophthalmology department of Desgenettes military hospital in Lyon, France. Eyes that underwent cataract surgery with Claeron® implantation were consecutively included. Patients with a systemic or ocular condition that could affect the visual outcome were excluded. Postoperative corrected (CDVA) and uncorrected (UDVA) distance visual acuities as well as capsule and IOL transparency were assessed at 1 month and 3 years. Results A total of 326 eyes were analyzed at one month and 191 eyes were reassessed at the 3-year follow-up visit. At 3 years, the mean CDVA was 0.003 LogMAR (95% confidence interval [CI]: -0.003 to -0.01) and the mean UDVA was 0.075 (95% CI: 0.054 to 0.095). Three quarters of the patients had an UDVA ≥ 0.097 logMAR (20/25 Snellen equivalent) and 50% had an UDVA ≥ 0 (20/20). The absence of glistening was reported in 95.3% of cases and 4.7% [9] of patients experienced a clinically significant posterior capsular opacification (PCO) for which Nd:YAG treatment was required. Conclusions This real-life study reports high-performance and stable long-term refractive outcomes of the Clareon® IOL with good safety in terms of PCO and glistening.

Published
2024
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8. Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

Author

Jessica Becker, Julia Bay, Deepa Ajit, Sheryl S. Moy, Katja Kloth, Michael T. Zimmermann, Pilar Cacheiro, Ingrid M.B.H. van de Laar, Richard H. van Jaarsveld, Queenie K-G Tan, Adriana S. Beltran, Allyn McConkie-Rosell, Keith A. Breau, Laura Schultz-Rogers, Deike Weiss, Damaris N Lorenzo, Marie T. McDonald, Robert Jech, Paul R. Mark, Erin Torti, Richard E. Person, Benjamin Cogné, Renske Oegema, Eva H. Brilstra, Robert Stratton, Koen L.I. van Gassen, Reginald James Edwards, Rebecca C. Spillmann, Michael C. Stankewich, Amy Kritzer, Liset Falcon Rodriguez, Parul Jayakar, Joseph T. Shieh, Margot A. Cousin, Elizabeth A. Normand, Jennifer L. Kemppainen, Jennifer MacKenzie, Hartmut Engels, Marjon van Slegtenhorst, Evangeline Kurtz-Nelson, Tianyun Wang, Yue Si, Damian Smedley, Bertrand Isidor, Blake A Creighton, Vimla Aggarwal, Michael Zech, Alvaro A. Beltran, Stefan Aretz, Brenda Temple, Simone Afriyie, Sarah E McKeown, Louise Bier, Tatjana Bierhals, Grace Yoon, Juliane Winkelmann, Swarnendu Tripathi, Brendan C. Lanpher, Amy Blevins, Pavel N. Pichurin, Eric W. Klee, Kathryn M. Harper, Cecilia Fairley, Lauren Gunderson, Ingo Helbig, Sruthi Dontu, Kirsten Cremer, Raphael Bernier, Helen V. Firth, Gretchen Parsons, Lorena J. Munoz, Evan E. Eichler, Alison S May, Grazia M.S. Mancini, and Clinical Genetics

Subjects
Heterozygote, Cytoskeleton organization, macromolecular substances, Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Intellectual disability, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Genetic Association Studies, 030304 developmental biology, Genes, Dominant, 0303 health sciences, Genetic Variation, Spectrin, Heterozygote advantage, medicine.disease, Phenotype, Hypotonia, Neurodevelopmental Disorders, Autism, medicine.symptom, Haploinsufficiency, Neuroscience, Neural development, 030217 neurology & neurosurgery
Abstract

SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system. SPTBN1 mutations cause a neurodevelopmental syndrome characterized by intellectual disability, language and motor delays, autism, seizures and other features. The variants disrupt βII-spectrin function and disturb cytoskeletal organization and dynamics.

Published
2021

9. Reflections on the genetics-first approach to advancements in molecular genetic and neurobiological research on neurodevelopmental disorders

Author

Anne B. Arnett, Tianyun Wang, Raphael Bernier, and Evan E. Eichler

Subjects
medicine.medical_specialty, Autism Spectrum Disorder, Cognitive Neuroscience, Population, Neurosciences. Biological psychiatry. Neuropsychiatry, Review, Biology, Genetics-first, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Neurobiology, Molecular genetics, Intellectual Disability, Intellectual disability, medicine, Humans, education, Gene, Molecular Biology, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Genomics, medicine.disease, Phenotype, Human genetics, Excitatory/inhibitory, Autism spectrum disorder, Neurodevelopmental Disorders, Pediatrics, Perinatology and Child Health, Identification (biology), Neurology (clinical), 030217 neurology & neurosurgery, RC321-571
Abstract

Background Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are common diagnoses with highly heterogeneous phenotypes and etiology. The genetics-first approach to research on NDDs has led to the identification of hundreds of genes conferring risk for ASD, ID, and related symptoms. Main body Although relatively few individuals with NDDs share likely gene-disruptive (LGD) mutations in the same gene, characterization of overlapping functions, protein networks, and temporospatial expression patterns among these genes has led to increased understanding of the neurobiological etiology of NDDs. This shift in focus away from single genes and toward broader gene–brain–behavior pathways has been accelerated by the development of publicly available transcriptomic databases, cell type-specific research methods, and sequencing of non-coding genomic regions. Conclusions The genetics-first approach to research on NDDs has advanced the identification of critical protein function pathways and temporospatial expression patterns, expanding the impact of this research beyond individuals with single-gene mutations to the broader population of patients with NDDs.

Published
2021

10. Family-based exome sequencing and case-control analysis implicate CEP41 as an ASD gene

Author

Wendy H. Raskind, Ryan R. Nesbitt, Ashok Patowary, So Yeon Won, Marilyn Archer, Raphael Bernier, Ji Eun Lee, Deborah A. Nickerson, Shin Ji Oh, and Zoran Brkanac

Subjects
Male, 0301 basic medicine, Autism Spectrum Disorder, Mutation, Missense, Biology, behavioral disciplines and activities, Article, Joubert syndrome, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neurodevelopmental disorder, Exome Sequencing, mental disorders, medicine, Animals, Humans, Missense mutation, Exome, Genetic Predisposition to Disease, Gene, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Zebrafish, Biological Psychiatry, Exome sequencing, Family Health, Genetics, Behavior, Animal, High-Throughput Nucleotide Sequencing, Proteins, Cell projection organization, medicine.disease, Disease Models, Animal, Psychiatry and Mental health, 030104 developmental biology, Autism spectrum disorder, Case-Control Studies, Autism, Female, 030217 neurology & neurosurgery
Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. Although next-generation sequencing (NGS) technologies have been successfully applied to gene identification in de novo ASD, the genetic architecture of familial ASD remains largely unexplored. Our approach, which leverages the high specificity and sensitivity of NGS technology, has focused on rare variants in familial autism. We used NGS exome sequencing in 26 families with distantly related affected individuals to identify genes with private gene disrupting and missense variants of interest (VOI). We found that the genes carrying VOIs were enriched for biological processes related to cell projection organization and neuron development, which is consistent with the neurodevelopmental hypothesis of ASD. For a subset of genes carrying VOIs, we then used targeted NGS sequencing and gene-based variant burden case-control analysis to test for association with ASD. Missense variants in one gene, CEP41, associated significantly with ASD (p = 6.185e−05). Homozygous gene-disrupting variants in CEP41 were initially found to be responsible for recessive Joubert syndrome. Using a zebrafish model, we evaluated the mechanism by which the CEP41 variants might contribute to ASD. We found that CEP41 missense variants affect development of the axonal tract, cranial neural crest migration and social behavior phenotype. Our work demonstrates the involvement of CEP41 heterozygous missense variants in ASD and that biological processes involved in cell projection organization and neuron development are enriched in ASD families we have studied.

Published
2019

11. A genetics-first approach to dissecting the heterogeneity of autism: phenotypic comparison of autism risk copy number variants

Author

Carrie E. Bearden, Marianne Bernadette van den Bree, Samuel J.R.A. Chawner, Leila Kushan, Louise Gallagher, Jeremy Hall, Wendy R. Kates, Kevin M. Antshel, Joanne L. Doherty, Judith S Miller, Caitlin C. Clements, Hayley Moss, Goran Cuturilo, A. Maillard, Raquel E. Gur, Sarah R Curran, LeeAnne Green-Snyder, Tara L. Wenger, Wendy K Chung, Michael J Owen, Richard Anney, Jacob Vorstman, Robert T. Schultz, Milica Pejovic-Milovancevic, Robin P. Goin-Kochel, Sébastien Jacquemont, Ellen Hanson, D M McDonald-McGinn, Raphael Bernier, Marina Mihaljevic, and Ania M Fiksinski

Subjects
Male, Heterozygote, DNA Copy Number Variations, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Interview, Psychological, Gene duplication, mental disorders, Prevalence, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Autistic Disorder, Child, Genetic Association Studies, Intelligence quotient, business.industry, medicine.disease, Phenotype, 030227 psychiatry, Psychiatry and Mental health, Trait, Etiology, Autism, business, Genetic diagnosis, Gene Deletion, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Objective: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.\ud \ud Methods: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing.\ud \ud Results: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits.\ud \ud Conclusions: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.

Published
2021

12. Sleep Problems in Children with ASD and Gene Disrupting Mutations

Author

Jennifer Gerdts, Tracey Ward, Raphael Bernier, Caitlin M. Hudac, Evan E. Eichler, and Rachel K. Earl

Subjects
Adult, Sleep Wake Disorders, Adolescent, Autism Spectrum Disorder, Nerve Tissue Proteins, behavioral disciplines and activities, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetic etiology, Sleep difficulties, mental disorders, Developmental and Educational Psychology, medicine, Humans, Life-span and Life-course Studies, Child, Gene, 030304 developmental biology, Homeodomain Proteins, Problem Behavior, 0303 health sciences, medicine.disease, Sleep in non-human animals, Clinical Psychology, Autism spectrum disorder, Child, Preschool, Mutation, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Sleep difficulties are pervasive in autism spectrum disorder (ASD), yet how sleep problems relate to underlying biological mechanisms such as genetic etiology is unclear, despite recent reports of profound sleep problems in children with ASD-associated de novo likely gene disrupting (dnLGD) mutations, CHD8, DYRK1A, and ADNP. We aimed to inform etiological contributions to ASD and sleep by characterizing sleep problems in individuals with dnLGD mutations. Participants (N = 2886) were families who completed dichotomous questions about sleep problems within a medical history interview for their child with ASD (age 3–28 years). Confirmatory factor analyses compared between those with ASD and a dnLGD mutation and those with idiopathic ASD (i.e., no known genetic event, NON) highlighted four domains (sleep onset, breathing issues, nighttime awakenings, and daytime tiredness) with sleep onset as a strong factor for both groups. Overall, participant predictors indicated that internalizing behavioral problems and lower cognitive scores were related to increased sleep problems. Internalizing problems were also related to increase nighttime awakenings in the dnLGD group. As an exploratory aim, patterns of sleep issues are described for genetic subgroups with unique patterns including more overall sleep issues in ADNP (n = 19), problems falling asleep in CHD8 (n = 22), and increased daytime naps in DYRK1A (n = 23). Implications for considering genetically defined subgroups when approaching sleep problems in children with ASD are discussed.

Published
2021

13. Associations between Self-Injurious Behaviors and Abdominal Pain among Individuals with ASD-Associated Disruptive Mutations

Author

Evangeline Kurtz-Nelson, Evan E. Eichler, Daniel Cho, Arianne S. Wallace, Kaitlyn Ahlers, Rachel K. Earl, See Wan Tham, and Raphael Bernier

Subjects
Abdominal pain, Autism Spectrum Disorder, Population, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Intellectual disability, Developmental and Educational Psychology, medicine, Humans, 0501 psychology and cognitive sciences, Genetic risk, education, Adaptive behavior, education.field_of_study, 05 social sciences, Cognition, social sciences, medicine.disease, Abdominal Pain, Autism spectrum disorder, Mutation, Autism, medicine.symptom, Psychology, Self-Injurious Behavior, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Clinical psychology
Abstract

Self-injurious behaviors (SIB) are elevated in autism spectrum disorder (ASD) and related genetic disorders, but the genetic and biological mechanisms that contribute to SIB in ASD are poorly understood. This study examined rates and predictors of SIB in 112 individuals with disruptive mutations to ASD-risk genes. Current SIB were reported in 30% of participants and associated with poorer cognitive and adaptive skills. History of severe abdominal pain predicted higher rates of SIB and SIB severity after controlling for age and adaptive behavior; individuals with a history of severe abdominal pain were eight times more likely to exhibit SIB than those with no history. Future research is needed to examine associations between genetic risk, pain, and SIB in this population.

Published
2020

14. NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism

Author

Kun Xia, Samantha Ayres, Amber Begtrup, Danielle Karlowicz, Raphael Bernier, Ahood Alsulaiman, Frédéric Bilan, Rebecca Hernan, Elena Savva, Fowzan S. Alkuraya, Ingrid M. Wentzensen, Mohammad A. Al-Muhaizea, Audrey Labalme, Sumit Punj, Jenny Meylan Merlini, Evan E. Eichler, Lucile Letienne-Cejudo, Alexia Boizot, Natasha J Brown, Emily Bryant, Senwei Tan, Wendy K. Chung, Bin Yu, Inken Dreyer, Maria J. Guillen Sacoto, Jieqiong Tan, Hilde Peeters, Xiangbin Jia, Inge Lore Ruiz-Arana, Brina Daniels, Elizabeth A. Sellars, Linda Pons, Jianjun Ou, Rujia Dai, Guodong Chen, Gaetan Lesca, Lindsay Rhodes, Anne chun-hui Tsai, Chao Chen, Marie T. McDonald, Linda Laux, Kendra Hoekzema, Hui Guo, Christina Fagerberg, Bradley Schaefer, Huidan Wu, Rhonda E. Schnur, Qiumeng Zhang, Federico Santoni, Qian Pan, Rose B. McGee, Lucia Bartoloni, Brigitte Gilbert-Dussardier, Zhengmao Hu, Charlotte Brasch-Andersen, Dhamidhu Eratne, Valerie Slegesky, and Lori A. Carpenter

Subjects
Male, Autism Spectrum Disorder, Gene Expression, Variable Expression, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Genotype-phenotype distinction, Pregnancy, Intellectual disability, Protein Isoforms, RNA, Small Interfering, Child, de novo variants, Genetics (clinical), Cerebral Cortex, Mice, Knockout, Neurons, 0303 health sciences, Learning Disabilities, Phenotype, Pedigree, Autism spectrum disorder, Female, Neuroglia, Adolescent, Genotype, autism spectrum disorder, genotype-phenotype correlation, Biology, Article, 03 medical and health sciences, Young Adult, Intellectual Disability, Genetics, medicine, Animals, Humans, Loss function, 030304 developmental biology, Adaptor Proteins, Signal Transducing, disruptive variant, medicine.disease, neurodevelopmental disorder, NCKAP1, HEK293 Cells, Mutation, Autism, Transcriptome, Neuroscience, 030217 neurology & neurosurgery
Abstract

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.

Published
2020

15. Late fMRI Response Components Are Altered in Autism Spectrum Disorder

Author

Tamar Kolodny, Michael-Paul Schallmo, Raphael Bernier, Jennifer Gerdts, and Scott O. Murray

Subjects
genetic structures, Neural Inhibition, autism, Stimulation, Sensory system, Inhibitory postsynaptic potential, behavioral disciplines and activities, lcsh:RC321-571, Behavioral Neuroscience, mental disorders, medicine, excitation-inhibition balance, undershoot, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Original Research, business.industry, Human Neuroscience, neural excitability, medicine.disease, Psychiatry and Mental health, Brain region, Neuropsychology and Physiological Psychology, Neurology, Autism spectrum disorder, Autism, functional MRI, business, Neuroscience, Neurotypical, offset response
Abstract

Disrupted cortical neural inhibition has been hypothesized to be a primary contributor to the pathophysiology of autism spectrum disorder (ASD). This hypothesis predicts that ASD will be associated with an increase in neural responses. We tested this prediction by comparing fMRI response magnitudes to simultaneous visual, auditory, and motor stimulation in ASD and neurotypical (NT) individuals. No increases in the initial transient response in any brain region were observed in ASD, suggesting that there is no increase in overall cortical neural excitability. Most notably, there were widespread fMRI magnitude increases in the ASD response following stimulation offset, approximately 6-8 s after the termination of sensory and motor stimulation. In some regions, the higher fMRI offset response in ASD could be attributed to a lack of an "undershoot"-an often observed feature of fMRI responses believed to reflect inhibitory processing. Offset response magnitude was associated with reaction times (RT) in the NT group and may explain an overall reduced RT in the ASD group. Overall, our results suggest that increases in neural responsiveness are present in ASD but are confined to specific components of the neural response, are particularly strong following stimulation offset, and are linked to differences in RT.

Published
2020

16. Insufficient Evidence for 'Autism-Specific' Genes

Author

Kevin J. Mitchell, David T. Miller, John N. Constantino, Wendy K. Chung, Raphael Bernier, Christa Lese Martin, David H. Ledbetter, Thomas Bourgeron, Evan E. Eichler, Thomas D. Challman, Sébastien Jacquemont, Scott M. Myers, Huda Y. Zoghbi, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), University of Washington [Seattle], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Columbia University Irving Medical Center (CUIMC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Université de Montréal (UdeM), Boston Children's Hospital, Trinity College Dublin, Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, This work was supported, in part, by the National Institute of Mental Health (NIMH) and Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health (NIH), under award numbers R01MH074090, R01MH107431, and U01MH11970510 (D.H.L., C.L.M., S.M.M.), Institut Pasteur, Université de Paris, Fondation Bettencourt-Schueller (T.B.), the Simons Foundation Autism Research Initiative (W.K.C.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development award number U54 HD087011 (J.N.C.), NIH grant MH101221 (E.E.E.), and the Canadian Institute of Health Research Canada Research Chair, Canadian Institute of Health Research award number 400528, and NIMH award number U01 MH119690-01 (S.J.). E.E.E. is an investigator of the Howard Hughes Medical Institute. D.T.M. receives an honorarium to serve on the Medical Genetics Committee of the Simons Foundation Powering Autism Research (SPARK) project and receives salary support from NIH grant U41 HG006834 (a Unified Clinical Genomics Database). H.Y.Z. is an investigator of the Howard Hughes Medical Institute., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Computational biology, MESH: Genotype, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Genetics, medicine, Gene, MESH: Cohort Studies, Genetics (clinical), MESH: Autism Spectrum Disorder, MESH: Humans, MESH: Genetic Testing, Large effect size, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Phenotype, MESH: Reproducibility of Results, 030104 developmental biology, Autism spectrum disorder, ▪▪▪, Commentary, Autism, Psychology, 030217 neurology & neurosurgery, MESH: Uncertainty
Abstract

International audience; Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data.

Published
2020

17. Episignatures stratifying ADNP syndrome show modest correlation with phenotype

Author

Antonio Novelli, Silvia De Rubeis, Mara Parellada, Paige M. Siper, Christine M. Freitag, Danielle Mendonca, Dorothy E. Grice, Carmen Moreno, Raphael Bernier, Paras Garg, Evangeline Kurtz-Nelson, Anne B. Arnett, Andrew J. Sharp, Yunin Ludena-Rodriguez, Andreas G. Chiocchetti, Mafalda Barbosa, Irva Hertz-Picciotto, Tess Levy, Lara Tang, Michael S. Breen, Giulia Pascolini, Paola Grammatico, Flora Tassone, Alexander Kolevzon, Emanuele Agolini, Agatino Battaglia, Alicia García-Alcón, and Joseph D. Buxbaum

Subjects
0303 health sciences, Methylation, Biology, medicine.disease, Bioinformatics, Phenotype, Neuroprotection, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, Intellectual disability, DNA methylation, medicine, Epigenetics, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

ADNP syndrome, also known as Helsmoortel-van Der Aa syndrome, is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. ADNP syndrome is caused by mutations in the activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with ADNP syndrome, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with ADNP syndrome into two groups, based on the location of the mutations. Here, we conducted an independent study on 24 individuals with ADNP syndrome and replicated the existence of the two, mutation-dependent ADNP episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of ADNP syndrome. We found limited phenotypic differences between the two ADNP groups, and no evidence that individuals with more widespread methylation changes are more severely affected. Also, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with ADNP syndrome. Our data warrant caution in harnessing methylation signatures in ADNP syndrome as a tool for clinical stratification, at least with regards to behavioral phenotypes.

Published
2020
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18. Co-occurring medical conditions among individuals with ASD-associated disruptive mutations

Author

Evangeline Kurtz-Nelson, Caitlin M. Hudac, Jennifer Gerdts, Kendra Hoekzema, Raphael Bernier, Arianne S. Wallace, Evan E. Eichler, and Jennifer S. Beighley

Subjects
Pediatrics, medicine.medical_specialty, genetic structures, business.industry, 05 social sciences, MEDLINE, medicine.disease, Medical care, behavioral disciplines and activities, Article, 03 medical and health sciences, Clinical Psychology, 0302 clinical medicine, Co occurring, Autism spectrum disorder, Gastrointestinal problems, 030225 pediatrics, Pediatrics, Perinatology and Child Health, mental disorders, Developmental and Educational Psychology, medicine, 0501 psychology and cognitive sciences, business, 050104 developmental & child psychology
Abstract

Children with autism spectrum disorder (ASD) are at risk for co-occurring medical conditions, many of which have also been reported among individuals with mutations in ASD-associated genes. This study examined rates of co-occurring medical conditions across 301 individuals with disruptive mutations to 1 of 18 ASD-risk genes in comparison to rates of conditions in an idiopathic ASD sample. Rates of gastrointestinal problems, seizures, physical anomalies, and immune problems were generally elevated, with significant differences in rates observed between groups. Results may inform medical care of individuals with ASD-associated mutations and research into mechanisms of co-occurring medical conditions in ASD.

Published
2020

19. A framework for an evidence-based gene list relevant to autism spectrum disorder

Author

Peter Szatmari, Mayada Elsabbagh, Wendy K. Chung, Helen V. Firth, Ny Hoang, Jacques L. Michaud, Catalina Betancur, Janet A. Buchanan, Jennifer L. Howe, Jacob A. S. Vorstman, Louise Gallagher, Christian P. Schaaf, Edwin H. Cook, Joseph D. Buxbaum, Kira A. Dies, Olivia Rennie, Stephen W. Scherer, Raphael Bernier, Jeremy R. Parr, Ryan K. C. Yuen, Patrick Bolton, Thomas W. Frazier, Christian R. Marshall, Chun-An Chen, David Skuse, Betancur, Catalina, Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, Newcastle University [Newcastle], University College of London [London] (UCL), Trinity College Dublin, University of Washington [Seattle], Children's Autism Center [Seattle, WA, USA], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Neurology, Children's Hospital [Boston], Boston Children's Hospital, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], Autism Speaks [Cleveland, OH, USA], Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Centre for Addiction and Mental Health [Toronto] (CAMH), Columbia University Medical Center (CUMC), Columbia University [New York], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Illinois [Chicago] (UIC), University of Illinois System, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa [Ottawa], Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU Sainte-Justine [Montreal], and CHU Sainte Justine [Montréal]-Université de Montréal (UdeM)

Subjects
Evidence-based practice, Research groups, Autism Spectrum Disorder, MEDLINE, MESH: Cognition, Computational biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, behavioral disciplines and activities, MESH: Intellectual Disability, 03 medical and health sciences, MESH: Brain, Cognition, 0302 clinical medicine, Intellectual Disability, mental disorders, Genetics, medicine, Humans, Molecular Biology, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, MESH: Genetic Association Studies, MESH: Autism Spectrum Disorder, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Evidence-Based Medicine, MESH: Humans, Extramural, Brain, Evidence-based medicine, medicine.disease, Clinical Practice, Autism spectrum disorder, Gene list, 030217 neurology & neurosurgery, MESH: Evidence-Based Medicine
Abstract

International audience; Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

Published
2020

20. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

Author

Charles E. Schwartz, Marjolein H. Willemsen, Saadet Mercimek-Andrews, Amy B. Wilfert, Hugo J. Bellen, Alexander P.A. Stegmann, Tjitske Kleefstra, Pawel Stankiewicz, Benjamin Büttner, Hailun Ni, Rongjuan Zhao, Rami Abou Jamra, Mariëtte J.V. Hoffer, Kristin Herman, Marjan M. Weiss, Heather C Mefford, Huidan Wu, Deanna J. Erwin, Zhengmao Hu, Claudia A. L. Ruivenkamp, Helger G. Yntema, Cindy Colson, Alessandra Murgia, Maria Bottitta, Jane Juusola, Tianyun Wang, Stephen M. Malone, Kun Xia, Baosheng Zhu, Nicolas Richard, Jozef Gecz, Elisa Bettella, Tuula Rinne, Raphael Bernier, Emilia K. Bijlsma, Michael F. Wangler, Shinya Yamamoto, Brigid M. Regan, Sharayu Jangam, Bregje W.M. van Bon, Jill A. Rosenfeld, Kendra Hoekzema, Cenying Liu, Shweta U. Dhar, Stefano Sartori, Boris Keren, Hui Guo, Lucia Castiglia, Servi J. C. Stevens, Corrado Romano, Min Long, Tomasz J. Nowakowski, Evan E. Eichler, Jan Maarten Cobben, Alison M. Muir, Lisa Emrick, Quinten Waisfisz, Wenjing Zhao, Jonathan C. Andrews, Ingrid E. Scheffer, Bing Bai, Madelyn A. Gillentine, Paul C. Marcogliese, Fan Xia, Han G. Brunner, Alexandra Afenjar, Academic Medical Center, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Klinische Genetica, Chinese Academy of Forestry, University Hospital of Padua, Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Central South University [Changsha], University of California, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Radboud University Medical Center [Nijmegen], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Ecosystèmes méditerranéens et risques (UR EMAX), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), The Greenwood Genetic Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Kunming University of Science and Technology (KMUST), The Hospital for sick children [Toronto] (SickKids), University of Toronto, GeneDx [Gaithersburg, MD, USA], Universität Leipzig [Leipzig], University of Melbourne, Queensland Institute of Medical Research, University of Adelaide, Emma Children’s Hospital, Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), The Chinese University of Hong Kong [Hong Kong], and Human genetics

Subjects
0301 basic medicine, Proband, Male, Genetics of the nervous system, Developmental Disabilities, General Physics and Astronomy, Muscle Proteins, medicine.disease_cause, ANNOTATION, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Whole Exome Sequencing, Craniofacial Abnormalities, Epilepsy, 0302 clinical medicine, Postsynaptic potential, Intellectual disability, Drosophila Proteins, lcsh:Science, Child, SYNAPTIC DEVELOPMENT, Neurons, Mutation, Multidisciplinary, Behavior, Animal, Mental Disorders, Brain, Drosophila melanogaster, Child, Preschool, Behavioural genetics, Excitatory postsynaptic potential, Female, Neuroglia, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, GENES, Adolescent, Science, Nerve Tissue Proteins, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, RESOURCE, Intellectual Disability, Exome Sequencing, medicine, Animals, Humans, Language Development Disorders, Autistic Disorder, Psychiatry, Preschool, [SDV.GEN]Life Sciences [q-bio]/Genetics, Behavior, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Animal, MEMORY, Membrane Proteins, Proteins, General Chemistry, medicine.disease, FRAMEWORK, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Neurodevelopmental Disorders, Neuronal development, Autism, lcsh:Q, business, Postsynaptic density, 030217 neurology & neurosurgery
Abstract

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2—whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes., Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.

Published
2019

21. Longitudinal report of child with de novo 16p11.2 triplication

Author

Caitlin M. Hudac, Trent D. DesChamps, Jessica L. Peterson, Kyle J. Steinman, Arianne S. Wallace, Michael H. Duyzend, Raphael Bernier, Xander Nuttle, and Evan E. Eichler

Subjects
0301 basic medicine, Genetics, business.industry, Case Report, 16p11.2 deletion, General Medicine, Case Reports, medicine.disease, Penetrance, Phenotype, 03 medical and health sciences, 16p11.2 duplication, 030104 developmental biology, Autism spectrum disorder, 16p11.2 triplication, medicine, ASD risk variant, gene triplication, business, Neurocognitive
Abstract

Key Clinical Message 16p11.2 deletions and duplications are commonly associated with autism spectrum disorder and linked to mirrored phenotypes of physical characteristics and higher penetrance for deletions. A male with a rare 16p11.2 triplication demonstrated a similar phenotypic presentation to deletion carriers with neurocognitive and adaptive skill deficits and above‐average physical growth.

Published
2017

22. Exploring the heterogeneity of neural social indices for genetically distinct etiologies of autism

Author

Emily Neuhaus, Raphael Bernier, Trent D. DesChamps, Susan Faja, Sara Jane Webb, Holly A.F. Stessman, Anna Kresse, Evan E. Eichler, and Caitlin M. Hudac

Subjects
0301 basic medicine, Social perception, Cognitive Neuroscience, Electroencephalography, Mu rhythm attenuation, Pathology and Forensic Medicine, Likely gene-disrupting mutations, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Social cognition, medicine, Habituation, Electroencephalography (EEG), lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, medicine.diagnostic_test, Research, Neuropsychology, Cognition, medicine.disease, Autism spectrum disorders (ASD), Human genetics, 030104 developmental biology, Autism spectrum disorder, Pediatrics, Perinatology and Child Health, Autism, Neurology (clinical), Psychology, Molecular subtyping, Neuroscience, 030217 neurology & neurosurgery
Abstract

Background Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous disorder. Promising initiatives utilizing interdisciplinary characterization of ASD suggest phenotypic subtypes related to specific likely gene-disrupting mutations (LGDMs). However, the role of functionally associated LGDMs in the neural social phenotype is unknown. Methods In this study of 26 children with ASD (n = 13 with an LGDM) and 13 control children, we characterized patterns of mu attenuation and habituation as children watched videos containing social and nonsocial motions during electroencephalography acquisition. Results Diagnostic comparisons were consistent with prior work suggesting aberrant mu attenuation in ASD within the upper mu band (10–12 Hz), but typical patterns within the lower mu band (8–10 Hz). Preliminary exploration indicated distinct social sensitization patterns (i.e., increasing mu attenuation for social motion) for children with an LGDM that is primarily expressed during embryonic development. In contrast, children with an LGDM primarily expressed post-embryonic development exhibited stable typical patterns of lower mu attenuation. Neural social indices were associated with social responsiveness, but not cognition. Conclusions These findings suggest unique neurophysiological profiles for certain genetic etiologies of ASD, further clarifying possible genetic functional subtypes of ASD and providing insight into mechanisms for targeted treatment approaches. Electronic supplementary material The online version of this article (doi:10.1186/s11689-017-9199-4) contains supplementary material, which is available to authorized users.

Published
2017

23. Within Visit Test-Retest Reliability of EEG Profiles in Children with Autism Spectrum Disorder and Typical Development

Author

Frederick Shic, Geraldine Dawson, Susan Faja, James C. McPartland, Damla Şentürk, Sara Jane Webb, Raphael Bernier, Charles A. Nelson, April R. Levin, Adam J. Naples, Katarzyna Chawarska, Catherine A. Sugar, Shafali S. Jeste, Aaron Scheffler, and Michael Murias

Subjects
medicine.diagnostic_test, Computer science, business.industry, 05 social sciences, Pattern recognition, Electroencephalography, medicine.disease, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Autism spectrum disorder, mental disorders, medicine, Autism, 0501 psychology and cognitive sciences, Artificial intelligence, business, 030217 neurology & neurosurgery
Abstract

Biomarker development is currently a high priority in neurodevelopmental disorder research. For many types of biomarkers (particularly biomarkers of diagnosis), reliability over short time periods is critically important. In the field of autism spectrum disorder (ASD), resting electroencephalography (EEG) power spectral densities (PSD) are well-studied for their potential as biomarkers. Classically, such data have been decomposed into pre-specified frequency bands (e.g., delta, theta, alpha, beta, and gamma). Recent technical advances, such as the Fitting Oscillations and One-Over-F (FOOOF) algorithm, allow for targeted characterization of the features that naturally emerge within an EEG PSD, permitting a more detailed characterization of the frequency band-agnostic shape of each individual’s EEG PSD. Here, using two resting EEGs collected a median of 6 days apart from 22 children with ASD and 25 typically developing (TD) controls during the Feasibility Visit of the Autism Biomarkers Consortium for Clinical Trials, we estimate within visit test-retest reliability based on characterization of the PSD shape in two ways: (1) Using the FOOOF algorithm we estimate six parameters (offset, slope, number of peaks, and amplitude, center frequency and bandwidth of the largest alpha peak) that characterize the shape of the EEG PSD; and (2) using nonparametric functional data analyses, we decompose the shape of the EEG PSD into a reduced set of basis functions that characterize individual power spectrum shapes. We show that individuals exhibit idiosyncratic PSD signatures that are stable over recording sessions using both characterizations. Our data show that EEG activity from a brief two-minute recording provides an efficient window into understanding brain activity at the single-subject level with desirable psychometric characteristics that persist across different analytical decomposition methods. This is a necessary step towards analytical validation of biomarkers based on the EEG PSD, and provides insights into parameters of the PSD that offer short-term reliability (and thus promise as potential biomarkers of trait or diagnosis) versus those that are more variable over the short term (and thus may index state or other rapidly dynamic measures of brain function). Future research should address longer-term stability of the PSD, for purposes such as monitoring development or response to treatment.

Published
2019
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24. Weaker neural suppression in autism

Author

Scott O. Murray, Rachel Millin, Anastasia V. Flevaris, Raphael Bernier, Alex Kale, Michael-Paul Schallmo, Richard A.E. Edden, Jennifer Gerdts, and Tamar Kolodny

Subjects
0301 basic medicine, Male, genetic structures, medicine.medical_treatment, Motion Perception, Visual Acuity, General Physics and Astronomy, 0302 clinical medicine, Cognition, Discrimination, Psychological, Attention, lcsh:Science, media_common, Brain Mapping, Multidisciplinary, 05 social sciences, Autism spectrum disorders, Magnetic Resonance Imaging, medicine.anatomical_structure, Autism spectrum disorder, Female, Psychology, Neurotypical, Adult, Sensory processing, Adolescent, Sensory Receptor Cells, media_common.quotation_subject, Science, Sensory system, Biology, behavioral disciplines and activities, 050105 experimental psychology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Young Adult, Perception, mental disorders, medicine, Biological neural network, Humans, 0501 psychology and cognitive sciences, Computer Simulation, Autistic Disorder, Mechanism (biology), General Chemistry, Inhibitory neurotransmitter, medicine.disease, 030104 developmental biology, Visual cortex, Autism, lcsh:Q, Visual system, Neuroscience, 030217 neurology & neurosurgery
Abstract

Abnormal sensory processing has been observed in autism, including superior visual motion discrimination, but the neural basis for these sensory changes remains unknown. Leveraging well-characterized suppressive neural circuits in the visual system, we used behavioral and fMRI tasks to demonstrate a significant reduction in neural suppression in young adults with autism spectrum disorder (ASD) compared to neurotypical controls. MR spectroscopy measurements revealed no group differences in neurotransmitter signals. We show how a computational model that incorporates divisive normalization, as well as narrower top-down gain (that could result, for example, from a narrower window of attention), can explain our observations and divergent previous findings. Thus, weaker neural suppression is reflected in visual task performance and fMRI measures in ASD, and may be attributable to differences in top-down processing., Sensory hypersensitivity is common in autism spectrum disorders. Using functional MRI, psychophysics, and computational modeling, Schallmo et al. show that differences in visual motion perception in ASD are accompanied by weaker neural suppression in visual cortex.

Published
2019
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25. Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero

Author

Shilpi Chabra, Erin M. Olson, Daniel A. Enquobahrie, Svante Östling, Henrik Hagberg, Kristina M. Adams Waldorf, Dominika Modzelewska, Lakshmi Rajagopal, Verena Sengpiel, Benjamin J. S. al-Haddad, Bo Jacobsson, and Raphael Bernier

Subjects
Adult, Male, Risk, Pediatrics, medicine.medical_specialty, Adolescent, Population, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pregnancy, medicine, Odds Ratio, Humans, Bipolar disorder, Registries, Pregnancy Complications, Infectious, education, Child, Depression (differential diagnoses), Original Investigation, Sweden, education.field_of_study, business.industry, Incidence, Mental Disorders, Hazard ratio, Infant, Newborn, Infant, Pregnancy infection, medicine.disease, 030227 psychiatry, Hospitalization, Psychiatry and Mental health, Schizophrenia, Child, Preschool, Prenatal Exposure Delayed Effects, Autism, Female, business, 030217 neurology & neurosurgery
Abstract

Importance The developmental origins of mental illness are incompletely understood. Although the development of autism and schizophrenia are linked to infections during fetal life, it is unknown whether more common psychiatric conditions such as depression might begin in utero. Objective To estimate the risk of psychopathologic conditions imparted from fetal exposure to any maternal infection while hospitalized during pregnancy. Design, Setting, and Participants A total of 1 791 520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries. Children were excluded if they were born too late to contribute person-time, died before being at risk for the outcome, or were missing particular model data. Infection and psychiatric diagnoses were derived using codes from hospitalizations. Directed acyclic graphs were developed from a systematic literature review to determine Cox proportional hazards regression models for risk of psychopathologic conditions in the children. Results were evaluated using probabilistic and simple bias analyses. Statistical analysis was conducted from February 10 to October 17, 2018. Exposures Hospitalization during pregnancy with any maternal infection, severe maternal infection, and urinary tract infection. Main Outcomes and Measures Inpatient diagnosis of autism, depression, bipolar disorder, or psychosis among offspring. Results A total of 1 791 520 Swedish-born children (48.6% females and 51.4% males) were observed from birth up to age 41 years, with a total of 32 125 813 person-years. Within the directed acyclic graph framework of assumptions, fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism (hazard ratio [HR], 1.79; 95% CI, 1.34-2.40) or depression (HR, 1.24; 95% CI, 1.08-1.42). Effect estimates for autism and depression were similar following a severe maternal infection (autism: HR, 1.81; 95% CI, 1.18-2.78; depression: HR, 1.24; 95% CI, 0.88-1.73) or urinary tract infection (autism: HR, 1.89; 95% CI, 1.23-2.90; depression: HR, 1.30; 95% CI, 1.04-1.61) and were robust to moderate unknown confounding. Within the directed acyclic graph framework of assumptions, the relationship between infection and depression was vulnerable to bias from loss to follow-up, but separate data from the Swedish Death Registry demonstrated increased risk of suicide among individuals exposed to pregnancy infection. No evidence was found for increased risk of bipolar disorder or psychosis among children exposed to infection in utero. Conclusions and Relevance These findings suggest that fetal exposure to a maternal infection while hospitalized increased the risk for autism and depression, but not bipolar or psychosis, during the child’s life. These results emphasize the importance of avoiding infections during pregnancy, which may impart subtle fetal brain injuries contributing to development of autism and depression.

Published
2019

26. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Author

Geraldine Dawson, Sven Sandin, Frederico Duque, Peter Holmans, Marion Leboyer, Aarno Palotie, Fritz Poustka, Richard Delorme, Stephen Sanders, Alistair T. Pagnamenta, Lonnie Zwaigenbaum, Bridget A. Fernandez, A. Jeremy Willsey, Christine M. Freitag, Christa Lese Martin, Elena Maestrini, Elena Bacchelli, Guiomar Oliveira, Jeremy R. Parr, Guy A. Rouleau, Jonas Bybjerg-Grauholm, Joseph Piven, Latha Soorya, Lauren A. Weiss, Jonathan Green, Carsten Bøcker Pedersen, Louise Gallagher, Regina Regan, Stephan Ripke, Thomas Werge, Pat Levitt, Aravinda Chakravarti, Joana Almeida, Kathryn Roeder, Catalina Betancur, Bernie Devlin, Benjamin M. Neale, Gillian Baird, Jakob Grove, Thomas Bourgeron, David H. Ledbetter, Eftichia Duketis, Karola Rehnström, Gerard D. Schellenberg, Jillian P. Casey, Preben Bo Mortensen, Patrick Bolton, Igor Martsenkovsky, Elise Robinson, Hakon Hakonarson, Vanessa H. Bal, Stacy Steinberg, Christopher Gillberg, Kathryn Tsang, Jacob A. S. Vorstman, Verneri Anttila, Suma Jacob, Judith Conroy, J. Haines, William M. McMahon, Edwin H. Cook, Ann P. Thompson, Inês C. Conceição, Mark J. Daly, Arthur P. Goldberg, Sarah E. Medland, Milica Pejovic-Milovancevic, David M. Hougaard, Shrikant Mane, Christina M. Hultman, Susana Mouga, Hreinn Stefansson, Ellen M. Wijsman, Andreas G. Chiocchetti, Ole Mors, Phil Lee, Richard Anney, Astrid M. Vicente, Veronica J. Vieland, K. Stefansson, Stephen W. Scherer, Teimuraz Silagadze, Pall Magnusson, Donna M. Martin, Merete Nordentoft, Peter Szatmari, Patrícia B. S. Celestino-Soper, Ann S Le-Couteur, Cátia Café, Arthur L. Beaudet, Kerstin Wittemeyer, Anders D. Børglum, Joel S. Bader, Christopher S. Poultney, Hailiang Huang, Alexander Kolevzon, Margaret A. Pericak-Vance, Joachim Hallmayer, Rita M. Cantor, Eric Fombonne, Andrew Green, Dan E. Arking, M. Daniele Fallin, Matthew W. State, Christine Ladd-Acosta, Silvia Derubeis, Raphael Bernier, Regina Waltes, David G. Amaral, Manuel Mattheisen, Abraham Reichenberg, Lambertus Klei, Daniel Moreno-De-Luca, Marie Bækvad-Hansen, Maretha V. Dejonge, Susan G. McGrew, Joseph D. Buxbaum, Hilary Coon, Jennifer Reichert, Michael Gill, Herman Vanengeland, Christine Søholm Hansen, Anthony P. Monaco, Nadia Bolshakova, John I. Nurnberger, Nancy J. Minshew, Michael T. Murtha, Thomas H. Wassink, Evald Saemundsen, Simon Wallace, Sean Brennan, Sean Ennis, A. Gulhan Ercan-Sencicek, Sven Bölte, Oscar Svantesson, Susan L. Santangelo, Andrew D. Paterson, Robert L. Hendren, Timothy W. Yu, Dalila Pinto, D.E. Grice, Alison Merikangas, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, Christopher A. Walsh, Susan E. Folstein, Wendy Roberts, Sabine M. Klauck, Marianne Giørtz Pedersen, Tiago R. Magalhaes, John R. Gilbert, Irva Hertz-Picciotto, James S. Sutcliffe, Evdokia Anagnostou, Catarina Correia, Eric M. Morrow, Daniel H. Geschwind, Jennifer K. Lowe, Agatino Battaglia, Bozenna Iliadou, Michael L. Cuccaro, Catherine Lord, MRC Centre for Neuropsychiatric Genetics and Genomics [Cardiff, UK], Cardiff University, The Autism Working Group of the Psychiatric Genomics Consortium was supported by National Institutes of Mental Health (NIMH, USA) grant MH109539, MH094432 and MH094421 to M.J.D. The ACE Network was supported by MH081754 and MH100027 to D.H.G. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) and was supported by grant MH081810. The Autism Genome Project (AGP) was supported by grants from Autism Speaks, the Canadian Institutes of Health Research (CIHR), Genome Canada, the Health Research Board (Ireland, AUT/ 2006/1, AUT/2006/2, PD/2006/48), the Hilibrand Foundation (USA), the Medical Research Council (UK), the National Institutes of Health (USA, the National Institute of Child Health and Human Development and the National Institute of Mental Health), the Ontario Genomics Institute, and the University of Toronto McLaughlin Centre. The Simons Simplex Collection (SSC) was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the Simons Simplex Collection Genetic Consortium), approved researchers can obtain the SSC population dataset described in this study (http://sfari.org/resources/sfari-base) by applying at https://base.sfari.org. The Gene Discovery Project of Johns Hopkins was funded by MH060007, MH081754, and the Simons Foundation. The MonBos Collection study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample (part of the MonBos collection) was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. The PAGES collection was funded by NIMH grant MH097849. The collection of data and biomaterials that participated in the NIMH Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219, and MH00980, National Health Medical Research Council grant 0034328, and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford), and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The iPSYCH project is funded by The Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. In addition, the genotyping of iPSYCH samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432-02 to MJD). The Study to Explore Early Development (SEED) was funded by the Centers for Disease Control and Prevention (CDC) grants U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, and U10DD000498. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Additional statistical analyses were performed and supported by the Trinity Centre for High Performance Computing (http://www.tchpc.tcd.ie/) funded through Science Foundation Ireland. Computational support for the PAGES collection was provided in part through the computational resources and staff expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (https://hpc.mssm.edu). Data QC and statistical analyses of the iPSYCH samples were performed at the high-performance computing cluster GenomeDK (http://genome.au.dk) at the Center for Integrative Sequencing, iSEQ, Aarhus University. iSEQ provided computed time, data storage, and technical support for the study., Richard JL Anney, Email: anneyr@cardiff.ac.uk, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK, Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Stephan Ripke, Email: ripke@atgu.mgh.harvard.edu, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany. Verneri Anttila, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Jakob Grove, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, DK-8000, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark, Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. Peter Holmans, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK. Hailiang Huang, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lambertus Klei, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Phil H Lee, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA. Sarah E Medland, Affiliation/s: Queensland Institute of Medical Research Brisbane, QLD, 4006, Australia. Benjamin Neale, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Elise Robinson, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lauren A Weiss, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Lonnie Zwaigenbaum, Affiliation/s: Department of Pediatrics, University of Alberta, Edmonton, AB, T6G 1C9, Canada. Timothy W Yu, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Kerstin Wittemeyer, Affiliation/s: School of Education, University of Birmingham, Birmingham, B15 2TT, UK. A.Jeremy Willsey, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Ellen M Wijsman, Affiliation/s: Department of Medicine, University of Washington, Seattle, WA 98195, USA, Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Thomas Werge, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Institute of Biological Psychiatry, MHC Sct Hans, Mental Health Services Copenhagen, Roskilde, Denmark, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK-2200, Denmark. Thomas H Wassink, Affiliation/s: Department of Psychiatry, Carver College of Medicine, Iowa City, IA 52242, USA. Regina Waltes, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher A Walsh, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA, Program in Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA, Simon Wallace, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK. Jacob AS Vorstman, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Veronica J Vieland, Affiliation/s: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children ’ s Hospital, Columbus, OH 43205, USA. Astrid M Vicente, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Herman vanEngeland, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Kathryn Tsang, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Ann P Thompson, Affiliation/s: Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, L8S 4L8, Canada. Peter Szatmari, Affiliation/s: Department of Psychiatry, University of Toronto, ON, M5T 1R8, Canada. Oscar Svantesson, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stacy Steinberg, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Kari Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Hreinn Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Matthew W State, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Latha Soorya, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, USA. Teimuraz Silagadze, Affiliation/s: Department of Psychiatry and Drug Addiction, Tbilisi State Medical University, Tbilisi, 0186, Georgia. Stephen W Scherer, Affiliation/s: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, McLaughlin Centre, University of Toronto, Toronto, ON, M5G 0A4, Canada, Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. Gerard D Schellenberg, Affiliation/s: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA. Sven Sandin, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stephan J Sanders, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Evald Saemundsen, Affiliation/s: State Diagnostic and Counseling Centre, Kopavogur, IS-201, Iceland. Guy A Rouleau, Affiliation/s: Montreal Neurological Institute, Dept of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada. Bernadette Rogé, Affiliation/s: Centre d ’ Etudes et de Recherches en Psychopathologie, Toulouse University, Toulouse, 31058, France. Kathryn Roeder, Affiliation/s: Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA, Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. Wendy Roberts, Affiliation/s: Autism Research Unit, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada. Jennifer Reichert, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Abraham Reichenberg, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Karola Rehnström, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK. Regina Regan, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Fritz Poustka, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher S Poultney, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Joseph Piven, Affiliation/s: University of North Carolina, Chapel Hill, NC 27599, USA. Dalila Pinto, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Margaret A Pericak-Vance, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Milica Pejovic-Milovancevic, Affiliation/s: Institute of Mental Health and Medical Faculty, University of Belgrade, Belgrade, 11 000, Serbia. Marianne Giørtz Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, National Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Carsten Bøcker Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Andrew D Paterson, Affiliation/s: Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, Dalla Lana School of Public Health, Toronto, ON, M5T 3M7, Canada. Jeremy R Parr, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Alistair T Pagnamenta, Affiliation/s: Wellcome Trust Centre for Human Genetics, OxfordUniversity,Oxford,OX37BN,UK. Guiomar Oliveira, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. John I Nurnberger, Affiliation/s: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Merete Nordentoft, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. Michael T Murtha, Affiliation/s: Programs on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA. Susana Mouga, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Preben Bo Mortensen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Na- tional Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark, Ole Mors, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. Eric M Morrow, Affiliation/s: Department of Psychiatry and Human Behaviour, Brown University, Providence, RI 02912, USA. Daniel Moreno-De-Luca, Affiliation/s: Department of Psychiatry and Hu- man Behaviour, Brown University, Providence, RI 02912, USA. Anthony P Monaco, Affiliation/s: Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK, Tufts University, Boston, MA 02155?, USA. Nancy Minshew, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Alison Merikangas, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. William M McMahon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Susan G McGrew, Affiliation/s: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA. Manuel Mattheisen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Igor Martsenkovsky, Affiliation/s: Department of Child, Adolescent Psychiatry and Medical-Social Rehabilitation, Ukrainian Research Institute of Social Fo- rensic Psychiatry and Drug Abuse, Kyiv, 04080, Ukraine. Donna M Martin, Affiliation/s: Department of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Shrikant M Mane, Affiliation/s: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06516, USA. Pall Magnusson, Affiliation/s: Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, IS-101, Iceland. Tiago Magalhaes, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Elena Maestrini, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Jennifer K Lowe, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Catherine Lord, Affiliation/s: Department of Psychiatry, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Pat Levitt, Affiliation/s: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. Christa LeseMartin, Affiliation/s: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, PA 17837, USA. David H Ledbetter, Affiliation/s: Chief Scientific Officer, Geisinger Health System, Danville, PA 17837, USA. Marion Leboyer, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, INSERM U955, Paris, 94010, France, Faculté de Médecine, Université Paris Est, Créteil, 94000, France, Department of Psychiatry, Henri Mondor-Albert Chene- vier Hospital, Assistance Publique – Hôpitaux de Paris, Créteil, 94000, France, Ann S LeCouteur, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Christine Ladd-Acosta, Affiliation/s: Department of Epidemiology, Johns Hop- kins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Alexander Kolevzon, Affiliation/s: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Sabine M Klauck, Affiliation/s: Division of Molecular Genome Analysis and Working Group Cancer Genome Research, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany. Suma Jacob, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA, Institute of Translational Neuroscience and Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA. Bozenna Iliadou, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Christina M Hultman, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. David M Hougaard, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Irva Hertz-Picciotto, Affiliation/s: Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA, The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA. Robert Hendren, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Christine Søholm Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Jonathan L Haines, Affiliation/s: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Stephen J Guter, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Dorothy E Grice, Affiliation/s: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Jonathan M Green, Affiliation/s: Manchester Academic Health Sciences Centre, Manchester, M13 9NT, UK, Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, M13 9PT, UK. Andrew Green, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Arthur P Goldberg, Affiliation/s: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Christopher Gillberg, Affiliation/s: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, S-405 30, Sweden. John Gilbert, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Louise Gallagher, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Christine M Freitag, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Eric Fombonne, Affiliation/s: Department of Psychiatry and Institute for Development and Disability, Oregon Health and Science University, Portland, OR 97239, USA. Susan E Folstein, Affiliation/s: Division of Child and Adolescent Psychiatry, Department of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Bridget Fernandez, Affiliation/s: Memorial University of Newfoundland, St John ’ s, NL, A1B 3X9, Canada. M.Daniele Fallin, Affiliation/s: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. A.Gulhan Ercan-Sencicek, Affiliation/s: Programs on Neurogenetics, Yale Uni- versity School of Medicine, New Haven, CT 06520, USA. Sean Ennis, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Frederico Duque, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Eftichia Duketis, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Richard Delorme, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, 75015, France, Centre National de la Recherche Scientifique URA 2182 Institut Pasteur, Paris, 75724, France, Department of Child and Adolescent Psychiatry, Robert Debré Hospital, Assistance Publique – Hôpitaux de Paris, Paris, 75019, France, Silvia DeRubeis, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Maretha V DeJonge, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Geraldine Dawson, Affiliation/s: Duke Center for Autism and Brain Developments, Duke University School of Medicine, Durham, NC 27705, USA, Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, NC 27708, USA. Michael L Cuccaro, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Catarina T Correia, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Judith Conroy, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Temple Street Children ’ s University Hospital, Dublin, D1, Ireland. Ines C Conceição, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Andreas G Chiocchetti, Affiliation/s: Depar tment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goe the University Frankfurt, Frankfurt am Main, 60528, Germany. Patrícia BS Celestino-Soper, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indian- apolis, IN 46202, USA. Jillian Casey, Affiliation/s: Temple Street Children ’ s University Hospital, Dublin, D1, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Rita M Cantor, Affiliation/s: Department of Psychiatry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA. Cátia Café, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Jonas Bybjerg-Grauholm, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Sean Brennan, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Thomas Bourgeron, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, University Paris Diderot, Sorbonne Paris Cité, Paris, 75013, France, Patrick F Bolton, Affiliation/s: Institute of Psychiatry, Kings College London, London, SE5 8AF, UK, South London and Maudsley Biomedical Research Centre for Mental Health, London, SE5 8AF, UK. Sven Bölte, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany, Department of Women ’ s and Children ’ s Health, Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, SE- 113 30, Sweden, Child and Adolescent Psychiatry, Center for Psychiatry Re- search, Stockholm County Council, Stockholm, SE-171 77, Sweden. Nadia Bolshakova, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Catalina Betancur, Affiliation/s: INSERM U1130, Paris, 75005, France, CNRS UMR 8246, Paris, 75005, France, Sorbonne Universités, UPMC Univ Paris 6, Neuroscience Paris Seine, Paris, 75005, France. Raphael Bernier, Affiliation/s: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. Arthur L Beaudet, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Agatino Battaglia, Affiliation/s: Stella Maris Institute for Child and Adolescent Neuropsychiatr, Pisa, 56018, Italy. Vanessa H Bal, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Gillian Baird, Affiliation/s: Paediatric Neurodisability, King ’ s Health Partners, Kings College London, London, SE1 7EH, UK. Anthony J Bailey, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK, Mental Health and Addictions Research Unit, University of British Colombia, Vancouver, BC, V5Z 4H4, Canada. Marie Bækvad-Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Joel S Bader, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Elena Bacchelli, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Evdokia Anagnostou, Affiliation/s: Bloorview Research Institute, University of Toronto, Toronto, ON, M4G 1R8, Canada. David Amaral, Affiliation/s: The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Psychiatry, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Behavioural Sciences, School of Medicine, University of California Davis, Davis, CA 95817, USA. Joana Almeida, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Anders D Børglum, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Joseph D Buxbaum, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Aravinda Chakravarti, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Edwin H Cook, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Hilary Coon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Daniel H Geschwind, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Michael Gill, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Hakon Hakonarson, Affiliation/s: The Center for Applied Genomics and Division of Human Genetics, Children ’ s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Dept of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA. Joachim Hallmayer, Affiliation/s: Department of Psychiatry, Stanford University, Stanford, CA 94305, USA. Aarno Palotie, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK., Anney, Richard J. L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertu, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thoma, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A. S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogã©, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnstrã¶m, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, Mcmahon, William M., Mcgrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceiã§ã£o, Ines C., Chiocchetti, Andreas G., Celestino-Soper, Patrícia B. S., Casey, Jillian, Cantor, Rita M., Cafã©, Cã¡tia, Bybjerg-Grauholm, Jona, Brennan, Sean, Bourgeron, Thoma, Bolton, Patrick F., Bã¶lte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Bã¸rglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, Daly, Mark J., Hakonarson, Hakon, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, INTELLECTUAL DISABILITY, Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, Autism, Neurodevelopment, Gene Expression, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, lcsh:RC346-429, 0302 clinical medicine, 2.1 Biological and endogenous factors, Pair 10, Copy-number variation, Aetiology, Autism spectrum disorder, Genetics, Adaptor Proteins, Forkhead Transcription Factors, Serious Mental Illness, 3. Good health, Mental Health, Psychiatry and Mental Health, Meta-analysis, Female, Biotechnology, Human, Autismo, Genetic correlation, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Gene-set analysi, Genomics, Locus (genetics), FOXP1, Biology, Chromosomes, Heritability, 03 medical and health sciences, Plasma Membrane Calcium-Transporting ATPases, Developmental Neuroscience, REVEALS, mental disorders, LINKAGE, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Meta-analysi, GENOME-WIDE ASSOCIATION, COMMON, Genotyping, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, COPY NUMBER VARIATION, Genetic association, Adaptor Proteins, Signal Transducing, Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 10, Research, Human Genome, Signal Transducing, Neurosciences, Membrane Proteins, medicine.disease, RISK LOCI, R1, Brain Disorders, Repressor Proteins, 030104 developmental biology, Genetic Loci, Case-Control Studies, Perturbações do Desenvolvimento Infantil e Saúde Mental, Schizophrenia, Carrier Proteins, Gene-set analysis, MENTAL-RETARDATION, SCAN, 030217 neurology & neurosurgery, Transcription Factors, Developmental Biology
Abstract

Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium - Collaborators (162): Anney RJL, Ripke S, Anttila V, Grove J, Holmans P, Huang H, Klei L, Lee PH, Medland SE, Neale B, Robinson E, Weiss LA, Zwaigenbaum L, Yu TW, Wittemeyer K, Willsey AJ, Wijsman EM, Werge T, Wassink TH, Waltes R, Walsh CA, Wallace S, Vorstman JAS, Vieland VJ, Vicente AM, vanEngeland H, Tsang K, Thompson AP, Szatmari P, Svantesson O, Steinberg S, Stefansson K, Stefansson H, State MW, Soorya L, Silagadze T, Scherer SW, Schellenberg GD, Sandin S, Sanders SJ, Saemundsen E, Rouleau GA, Rogé B, Roeder K, Roberts W, Reichert J, Reichenberg A, Rehnström K, Regan R, Poustka F, Poultney CS, Piven J, Pinto D, Pericak-Vance MA, Pejovic-Milovancevic M, Pedersen MG, Pedersen CB, Paterson AD, Parr JR, Pagnamenta AT, Oliveira G, Nurnberger JI, Nordentoft M, Murtha MT, Mouga S, Mortensen PB, Mors O, Morrow EM, Moreno-De-Luca D, Monaco AP, Minshew N, Merikangas A, McMahon WM, McGrew SG, Mattheisen M, Martsenkovsky I, Martin DM, Mane SM, Magnusson P, Magalhaes T, Maestrini E, Lowe JK, Lord C, Levitt P, Martin CL, Ledbetter DH, Leboyer M, LeCouteur AS, Ladd-Acosta C, Kolevzon A, Klauck SM, Jacob S, Iliadou B, Hultman CM, Hougaard DM, Hertz-Picciotto I, Hendren R, Hansen CS, Haines JL, Guter SJ, Grice DE, Green JM, Green A, Goldberg AP, Gillberg C, Gilbert J, Gallagher L, Freitag CM, Fombonne E, Folstein SE, Fernandez B, Fallin MD, Ercan-Sencicek AG, Ennis S, Duque F, Duketis E, Delorme R, DeRubeis S, DeJonge MV, Dawson G, Cuccaro ML, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Celestino-Soper PBS, Casey J, Cantor RM, Café C, Bybjerg-Grauholm J, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bolshakova N, Betancur C, Bernier R, Beaudet AL, Battaglia A, Bal VH, Baird G, Bailey AJ, Bækvad-Hansen M, Bader JS, Bacchelli E, Anagnostou E, Amaral D, Almeida J, Børglum AD, Buxbaum JD, Chakravarti A, Cook EH, Coon H, Geschwind DH, Gill M, Hallmayer J, Palotie A, Santangelo S, Sutcliffe JS, Arking DE, Devlin B, Daly MJ. Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA. PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/ Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR)

Published
2017

27. Auditory perception is associated with implicit language learning and receptive language ability in autism spectrum disorder

Author

Trent D. DesChamps, Sara J Webb, Jennifer Gerdts, Arianne S. Wallace, Anne B. Arnett, Caitlin M. Hudac, Raphael Bernier, and Brianna E. Cairney

Subjects
Auditory perception, Male, Linguistics and Language, medicine.medical_specialty, genetic structures, Adolescent, Auditory event, Autism Spectrum Disorder, Cognitive Neuroscience, Experimental and Cognitive Psychology, Audiology, behavioral disciplines and activities, Language Development, 050105 experimental psychology, Language and Linguistics, Article, 03 medical and health sciences, Speech and Hearing, 0302 clinical medicine, mental disorders, medicine, Humans, 0501 psychology and cognitive sciences, Child, Evoked Potentials, 05 social sciences, Cognition, Language acquisition, medicine.disease, Implicit learning, Language development, Autism spectrum disorder, Auditory Perception, Female, Psychology, 030217 neurology & neurosurgery, Neurotypical
Abstract

Background Autism spectrum disorder (ASD) is associated with language impairment as well as atypical auditory sensory processing. The current study investigated associations among auditory perception, implicit language learning and receptive language ability in youth with ASD. Methods We measured auditory event related potentials (ERP) during an artificial language statistical learning task in 76 youth with ASD and 27 neurotypical (NT) controls. Participants with ASD had a broad range of cognitive and language abilities. Results NT youth showed evidence of implicit learning via attenuated P1 amplitude in the left hemisphere. In contrast, among youth with ASD, implicit learning elicited bilateral attenuation that was increasingly evident with greater receptive language skill. Conclusions Efficient early auditory perception reflects language learning and is a marker of language ability among youth with ASD. Atypical lateralization of word learning is evident in ASD across a broad range of receptive language abilities.

Published
2018

28. Can a composite heart rate variability biomarker shed new insights about autism spectrum disorder in school-aged children?

Author

Theodore P. Beauchaine, Emily Neuhaus, Martin G. Frasch, Raphael Bernier, Dana Kamara, Hau-Tieng Wu, Chao Shen, and Alexander Mueller

Subjects
Male, medicine.medical_specialty, Autism Spectrum Disorder, Rest, Audiology, Quantitative Biology - Quantitative Methods, Machine Learning, Electrocardiography, 03 medical and health sciences, 0302 clinical medicine, Heart Rate, mental disorders, Developmental and Educational Psychology, medicine, Humans, Heart rate variability, 0501 psychology and cognitive sciences, Prospective Studies, Child, Students, Prospective cohort study, Quantitative Methods (q-bio.QM), Problem Solving, Schools, Receiver operating characteristic, 05 social sciences, medicine.disease, Autism spectrum disorder, Conduct disorder, FOS: Biological sciences, Quantitative Biology - Neurons and Cognition, Cohort, Biomarker (medicine), Autism, Neurons and Cognition (q-bio.NC), Female, Psychology, Biomarkers, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract

High-frequency heart rate variability (HRV) has identified parasympathetic nervous system alterations in autism spectrum disorder (ASD). In a cohort of school-aged children with and without ASD, we test a set of alternative linear and nonlinear HRV measures, including phase rectified signal averaging, applied to a segment of resting ECG, for associations with ASD vs. other psychiatric conditions. Using machine learning, we identify HRV measures derived from time, frequency, and geometric signal-analytical domains that (1) identify children with ASD relative to peers with receiver operating curve area of .89, and (2) differentiate such children from those with conduct problems or depression. Despite the small cohort and lack of prospective external validation, these preliminary results warrant larger prospective validation studies.

Published
2018

29. The Autism Spectrum Phenotype in ADNP Syndrome

Author

Anne B. Arnett, Jennifer Gerdts, Evan E. Eichler, Sandra Bedrosian-Sermone, Tychele N. Turner, Arianne S. Wallace, Candace Rhoads, Kendra Hoekzema, and Raphael Bernier

Subjects
0301 basic medicine, Adult, Male, Adolescent, Autism Spectrum Disorder, Stereotypic Movement Disorder, Nerve Tissue Proteins, Affect (psychology), behavioral disciplines and activities, Article, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Intellectual Disability, Intellectual disability, mental disorders, medicine, Humans, Child, Social Communication Disorder, Genetics (clinical), Homeodomain Proteins, business.industry, General Neuroscience, Syndrome, medicine.disease, Verbal reasoning, Hypotonia, Developmental disorder, 030104 developmental biology, Phenotype, Autism spectrum disorder, Child, Preschool, Cohort, Autism, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Pathogenic disruptions to the activity-dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD-associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4-22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD-associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits. Autism Res 2018, 11: 1300-1310. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment.

Published
2018

30. Glutamatergic facilitation of neural responses in MT enhances motion perception in humans

Author

Scott O. Murray, Michael-Paul Schallmo, Alex Kale, Tamar Kolodny, Richard A.E. Edden, Rachel Millin, and Raphael Bernier

Subjects
Adult, Male, Magnetic Resonance Spectroscopy, Cognitive Neuroscience, media_common.quotation_subject, Motion Perception, Glutamic Acid, Biology, Article, 050105 experimental psychology, 030218 nuclear medicine & medical imaging, Young Adult, 03 medical and health sciences, Glutamatergic, chemistry.chemical_compound, 0302 clinical medicine, Perception, Psychophysics, Motion direction, Humans, Visual Pathways, 0501 psychology and cognitive sciences, Motion perception, Neurotransmitter, Visual Cortex, media_common, Brain Mapping, 05 social sciences, Glutamate receptor, Magnetic Resonance Imaging, Neurology, chemistry, Facilitation, Female, Neuroscience, Photic Stimulation, 030217 neurology & neurosurgery
Abstract

There is large individual variability in human neural responses and perceptual abilities. The factors that give rise to these individual differences, however, remain largely unknown. To examine these factors, we separately measured fMRI responses to moving gratings in the motion-selective region MT, and perceptual duration thresholds for motion direction discrimination within the same group of male and female subjects. Further, we acquired MR spectroscopy data that allowed us to quantify an index of neurotransmitter levels in the region surrounding MT. We show that individual differences in the Glx (glutamate + glutamine) signal in the MT region are associated with both higher fMRI responses and improved psychophysical task performance. Our results suggest that individual differences in baseline levels of glutamate within MT contribute to motion perception by increasing neural responses in this region.SignificanceWhat factors govern the relationship between neural activity and behavior? Our results suggest that one such factor is the level of glutamate, an excitatory neurotransmitter, within a particular region of cortex. By measuring an index of glutamate in vivo using magnetic resonance spectroscopy, we show that human subjects with more glutamate in the visual motion area known as MT also have larger fMRI responses (an index of neural activity) in this region. Further, people with more glutamate in MT can accurately perceive moving images presented more briefly within a behavioral task. Our findings point to an important role for glutamate levels in determining the relationship between neural responses and behavior during visual motion perception.

Published
2018
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31. Sex differences in visual motion processing

Author

Michael-Paul Schallmo, Alex Kale, Philipp Thomas, Rachel Millin, Scott O. Murray, Tamar Kolodny, Thomas Rammsayer, Stefan J. Troche, Duje Tadin, and Raphael Bernier

Subjects
Adult, Male, medicine.medical_specialty, Visual perception, genetic structures, Adolescent, media_common.quotation_subject, Motion Perception, Context (language use), Audiology, Biology, 050105 experimental psychology, General Biochemistry, Genetics and Molecular Biology, Motion (physics), Article, Visual processing, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Sex Factors, Perception, medicine, Humans, 0501 psychology and cognitive sciences, Motion perception, media_common, 05 social sciences, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Autism spectrum disorder, Visual Perception, Female, Nerve Net, 370 Education, General Agricultural and Biological Sciences, 150 Psychology, 030217 neurology & neurosurgery, Neurotypical
Abstract

Summary The importance of sex as a biological variable has recently been emphasized by major funding organizations [ 1 ] and within the neuroscience community [ 2 ]. Critical sex-based neural differences are indicated by, for example, conditions such as autism spectrum disorder (ASD) that have a strong sex bias with a higher prevalence among males [ 51 , 3 ]. Motivated by this broader context, we report a marked sex difference in a visual motion perception task among neurotypical adults. Motion duration thresholds [ 4 , 5 ]—the minimum duration needed to accurately perceive motion direction—were considerably shorter for males than females. We replicated this result across three laboratories and 263 total participants. This type of enhanced performance has previously been observed only in special populations including ASD, depression, and senescence [ 6 , 7 , 8 ]. The observed sex difference cannot be explained by general differences in speed of visual processing, overall visual discrimination abilities, or potential motor-related differences. We also show that while individual differences in motion duration thresholds are associated with differences in fMRI responsiveness of human MT+, surprisingly, MT+ response magnitudes did not differ between males and females. Thus, we reason that sex differences in motion perception are not captured by an MT+ fMRI measure that predicts within-sex individual differences in perception. Overall, these results show how sex differences can manifest unexpectedly, highlighting the importance of sex as a factor in the design and analysis of perceptual and cognitive studies.

Published
2018
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33. Gene Disrupting Mutations Associated with Regression in Autism Spectrum Disorder

Author

Shelley Barber, Robin P. Goin-Kochel, Sandy Trinh, and Raphael Bernier

Subjects
0301 basic medicine, Adolescent, Autism Spectrum Disorder, Epigenetics of autism, medicine.disease_cause, behavioral disciplines and activities, Article, Developmental psychology, 03 medical and health sciences, Fragile X Mental Retardation Protein, 0302 clinical medicine, mental disorders, Developmental and Educational Psychology, medicine, Humans, Child, Gene, Exome, Genetics, Mutation, Genes, Essential, Post-Synaptic Density, medicine.disease, Phenotype, Chromatin, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Autism, Female, Psychology, Postsynaptic density, 030217 neurology & neurosurgery
Abstract

Approximately one third of children with autism spectrum disorder (ASD) reportedly lose skills within the first three years, yet a causal mechanism remains elusive. Considering evidence of strong genetic effects for ASD and findings that distinct phenotypes in ASD associate with specific genetic events, we examined rates of parent-reported regression in the Simons Simplex Collection with likely gene disrupting (LGD) mutations from five distinct classes: FMRP target genes, genes encoding chromatin modifiers, genes expressed preferentially in embryos, genes encoding postsynaptic density proteins, and essential genes. Children with ASD and mutations in postsynaptic density genes were more likely to experience regression, while a trend suggested that children with ASD and mutations in embryonic genes were less likely to have skill losses.

Published
2017

34. Clinical phenotype of ASD-associated DYRK1A haploinsufficiency

Author

Rachel K. Earl, Heather C Mefford, Evan E. Eichler, Tychele N. Turner, Raphael Bernier, Jennifer Gerdts, and Caitlin M. Hudac

Subjects
0301 basic medicine, Male, Microcephaly, Pediatrics, Neurology, Autism Spectrum Disorder, Autism, Genetically defined subtype, Haploinsufficiency, lcsh:RC346-429, Intellectual disability, Clinical phenotype, Child, Genetics, education.field_of_study, Neuropsychology, Protein-Tyrosine Kinases, Disruptive mutation, DNA-Binding Proteins, Psychiatry and Mental health, Phenotype, Child, Preschool, Speech delay, Female, medicine.symptom, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Population, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, 03 medical and health sciences, Developmental Neuroscience, Intellectual Disability, medicine, Humans, Language Development Disorders, education, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Research, DYRK1A, medicine.disease, 030104 developmental biology, Genetic syndrome, Developmental Biology, Transcription Factors
Abstract

Background DYRK1A is a gene recurrently disrupted in 0.1–0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. Methods Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. Results DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. Conclusions Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background. Electronic supplementary material The online version of this article (10.1186/s13229-017-0173-5) contains supplementary material, which is available to authorized users.

Published
2017

35. Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

Author

Brian J. O'Roak, Eric Fombonne, Raphael Bernier, Deidre R. Krupp, Yannis Duffourd, Sara A. Evans, Ryan M. Mulqueen, Jean Baptiste Rivière, Rebecca A. Barnard, Department of Molecular & Medical Genetics (Oregon Health & Science University, Portland), Oregon Health & Science University [Portland] ( OHSU ), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Psychiatry and Behavioral Sciences, University of Washington, Department of Human Genetics (McGill University, Montréal), McGill University, Department of Psychiatry (Oregon Health & Science University, Portland), Oregon Health and Science University [Portland] (OHSU), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of Human Genetics [Montréal], and McGill University = Université McGill [Montréal, Canada]

Subjects
Male, 0301 basic medicine, Proband, Zygote, autism spectrum disorder, SYNGAP1, Biology, postzygotic, medicine.disease_cause, Article, Germline, Cohort Studies, 03 medical and health sciences, splicing, 0302 clinical medicine, Neurodevelopmental disorder, Germline mutation, Databases, Genetic, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, neurodevelopment, somatic, Genetic Variation, Exons, medicine.disease, 030104 developmental biology, mosaicism, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, CHD2, Autism, Female, mutation, 030217 neurology & neurosurgery, exome
Abstract

Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. We systematically evaluated PMMs by leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection. We found evidence that 11% of published single nucleotide variant (SNV)de novomutations are potentially PMMs. We then developed a robust SNV PMM calling approach that leverages complementary callers, logistic regression modeling, and additional heuristics. Using this approach, we recalled SNVs and found that 22% ofde novomutations likely occur as PMMs in children. Unexpectedly, we found a significant burden of synonymous PMMs in probands that are predicted to alter splicing. We found no evidence of missense PMM burden in the full cohort. However, we did observe increased signal for missense PMMs in families without germline mutations in probands, which strengthens in genes intolerant to mutations. We also determined that 7-11% of parental mosaics are transmitted to children. Parental mosaic mutations make up 6.8% of all mutations newly germline in children, which has important implications for recurrence risk. PMMs intersect previously implicated high confidence and other ASD candidate risk genes, further suggesting that this class of mutations contribute to ASD risk. We also identified PMMs in novel candidate risk genes involved with chromatin remodeling or neurodevelopment. We estimate that PMMs contribute risk to 4-8% of simplex ASD cases. Overall, these findings argue for future studies of PMMs in ASD and related-disorders.

Published
2017

36. Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Author

Hakon Hakonarson, Tianyun Wang, Karen Pierce, Madeleine R. Geisheker, Antonino Alberti, Ann Nordgren, Britt-Marie Anderlid, Geert Vandeweyer, Mirella Vinci, Christopher Barnett, Kendra Hoekzema, Larry S. Zweifel, Jan Liebelt, Kun Xia, Anna Lindstrand, Raphael Bernier, Bradley P. Coe, Eric Haan, Elizabeth Thompson, Eric Courchesne, Malin Kvarnung, Kathryn Friend, Jozef Gecz, Marie Shaw, Holly A.F. Stessman, Tychele N. Turner, Tiziano Pramparo, Gijs W. E. Santen, Jacob J. Michaelson, Hui Guo, Gabriel Heymann, Corrado Romano, Magnus Nordenskjöld, Evan E. Eichler, Emanuela Avola, Stefania Giusto, R. Frank Kooy, Hilde Peeters, Zdenek Sedlacek, and Srinivasa Nalabolu

Subjects
Male, 0301 basic medicine, Candidate gene, Mutation, Missense, Biology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, medicine, Humans, Missense mutation, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Receptors, AMPA, Autistic Disorder, Gene, Genetics, Mutation, General Neuroscience, medicine.disease, Phenotype, 030104 developmental biology, Receptors, Glutamate, Female, Human medicine, Neuroscience, 030217 neurology & neurosurgery, GRID2
Abstract

Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

Published
2017

37. Suppression and facilitation of human neural responses

Author

Anastasia V. Flevaris, Richard A.E. Edden, Michael-Paul Schallmo, Rachel Millin, Raphael Bernier, Alex Kale, Scott O. Murray, and Zoran Brkanac

Subjects
Male, Magnetic Resonance Spectroscopy, Computer science, Surround suppression, Neural Inhibition, GABA, 0302 clinical medicine, Psychophysics, Biology (General), Visual Cortex, media_common, General Neuroscience, 05 social sciences, spatial vision, General Medicine, Healthy Volunteers, surround suppression, normalization, Neural processing, Facilitation, Medicine, Female, Research Article, Human, Adult, QH301-705.5, media_common.quotation_subject, Science, Models, Neurological, 050105 experimental psychology, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Neural activity, Physical Stimulation, Perception, Humans, 0501 psychology and cognitive sciences, Motion perception, Behavior, General Immunology and Microbiology, business.industry, motion perception, Visual motion, MT, Artificial intelligence, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Efficient neural processing depends on regulating responses through suppression and facilitation of neural activity. Utilizing a well-known visual motion paradigm that evokes behavioral suppression and facilitation, and combining 5 different methodologies (behavioral psychophysics, computational modeling, functional MRI, pharmacology, and magnetic resonance spectroscopy), we provide evidence that challenges commonly held assumptions about the neural processes underlying suppression and facilitation. We show that: 1) both suppression and facilitation can emerge from a single, computational principle – divisive normalization; there is no need to invoke separate neural mechanisms, 2) neural suppression and facilitation in the motion-selective area MT mirror perception, but strong suppression also occurs in earlier visual areas, and 3) suppression is not driven by GABA-mediated inhibition. Thus, while commonly used spatial suppression paradigms may provide insight into neural response magnitudes in visual areas, they cannot be used to infer neural inhibition.

Published
2017
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38. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Author

Bradley P. Coe, Christopher Barnett, Stefania Giusto, Arie van Haeringen, Marie Shaw, Kathryn Friend, Bo Xiong, Mirella Vinci, David G. Amaral, Tianyun Wang, Nele Cosemans, Emanuela Avola, R. Frank Kooy, Jan Liebelt, Karen Pierce, Ingrid E. Scheffer, Eric Courchesne, Anna Lindstrand, Anna Castells-Nobau, Jennifer Gerdts, Ann Nordgren, Annette Schenck, Charles E. Schwartz, Raphael Bernier, Tiziano Pramparo, Britt-Marie Anderlid, Michaela Fenckova, Malin Kvarnung, Laura Vives, Paul J. Lockhart, Céline Helsmoortel, Gijs W. E. Santen, Hilde Peeters, Marjolein Kriek, Benjamin Harich, Corrado Romano, Antonino Alberti, Magnus Nordenskjöld, Emmelien Aten, Srinivasa Nalabolu, Evan E. Eichler, Martin B. Delatycki, Janice Lin, Holly A.F. Stessman, Kun Xia, Kendra Hoekzema, Geert Vandeweyer, Jozef Gecz, Claudia A. L. Ruivenkamp, Eric Haan, Fereydoun Hormozdiari, Sandy Trinh, and Tychele N. Turner

Subjects
0301 basic medicine, Male, Candidate gene, Autism, Intellectual and Developmental Disabilities (IDD), Developmental Disabilities, Disease, Biology, medicine.disease_cause, Medical and Health Sciences, Article, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, Behavioral and Social Science, medicine, Genetics, 2.1 Biological and endogenous factors, Humans, Spectrum disorder, Genetic Testing, Aetiology, Autistic Disorder, Pediatric, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurosciences, Biological Sciences, medicine.disease, Phenotype, 3. Good health, Brain Disorders, 030104 developmental biology, Mental Health, Female, Human medicine, Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7], 030217 neurology & neurosurgery, Developmental Biology
Abstract

Item does not contain fulltext Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Published
2017

39. Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism

Author

Jennifer Gerdts, Evan E. Eichler, Tracey Ward, Kyleen Luhrs, Caitlin M. Hudac, Raphael Bernier, and Holly A.F. Stessman

Subjects
0301 basic medicine, medicine.medical_specialty, Article Subject, lcsh:RC435-571, behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, Genetic etiology, lcsh:Psychiatry, mental disorders, Gene duplication, medicine, Copy-number variation, Psychiatry, business.industry, General Medicine, Familial risk, medicine.disease, 030104 developmental biology, Autism spectrum disorder, dup, Autism, Anxiety, medicine.symptom, business, 030217 neurology & neurosurgery, Research Article
Abstract

The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD) with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP,n=62), de novo deletion copy number variations (DEL,n=74), de novo likely gene-disrupting mutations (LGDM,n=267), and children without a known genetic etiology (NON,n=2111). Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships.

Published
2017
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40. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Author

Sinje Geuer, Sally Ann Lynch, Joseph T. Shieh, Ruth Newbury-Ecob, Tjitske Kleefstra, Rachel Brough, Lisenka E.L.M. Vissers, Marja W. Wessels, Kristin G. Monaghan, Elysa J. Marco, Marjolein H. Willemsen, Rolph Pfundt, Priyanka Ghongane, Alice Gardham, Malin Kvarnung, Marjon van Slegtenhorst, E.A. Helena Magnusson, Johanna C. Herkert, Nicola K. Ragge, Sandra Jansen, Petra de Vries, Christopher J. Lord, Raphael Bernier, Mark C. Hannibal, Birgitta Bernhard, David R. FitzPatrick, Frances Flinter, Joris A. Veltman, Bert B.A. de Vries, Clinical Genetics, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, and Groei & Ontwikkeling

Subjects
0301 basic medicine, BLOOD, Adolescent, WIP1, Biology, Bioinformatics, medicine.disease_cause, DISEASE, Frameshift mutation, 03 medical and health sciences, Exon, Young Adult, Report, Intellectual Disability, Intellectual disability, SCHIZOPHRENIA, Journal Article, Genetics, medicine, Humans, AUTISM, Child, Gene, Genetics (clinical), Mutation, SPECTRUM, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], FRAMESHIFT, Cell Cycle, DOMINANT ROBINOW SYNDROME, Exons, medicine.disease, CANCER, GENE, Hypotonia, Protein Phosphatase 2C, 030104 developmental biology, Schizophrenia, Child, Preschool, Autism, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 174535.pdf (Publisher’s version ) (Closed access) Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in approximately 35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

Published
2017

41. De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

Author

Annette Schenck, Alexander Hoischen, Janneke H M Schuurs-Hoeijmakers, Ernie M.H.F. Bongers, Gemma L. Carvill, Sabine Kuenen, Arn M. J. M. van den Maagdenberg, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Joris A. Veltman, Claudia A. L. Ruivenkamp, Christian Gilissen, Raphael Bernier, Bregje W.M. van Bon, Patrik Verstreken, Anneke T. Vulto-van Silfhout, Dorien Lugtenberg, Gijs W. E. Santen, Daniëlle G.M. Bosch, Emilia K. Bijlsma, Eric Smeets, Petra de Vries, Rolph Pfundt, Heather C Mefford, Cacha M.P.C.D. Peeters-Scholte, Evan E. Eichler, Bert B.A. de Vries, Margot R.F. Reijnders, Helger G. Yntema, Michaela Fenckova, MUMC+: DA KG Polikliniek (9), Genetica & Celbiologie, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, and RS: GROW - R4 - Reproductive and Perinatal Medicine

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Candidate gene, Adolescent, Histone H2B ubiquitination, Biology, Bioinformatics, medicine.disease_cause, Article, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Craniofacial Abnormalities, Young Adult, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Animals, Drosophila Proteins, Humans, Learning, Child, Habituation, Psychophysiologic, Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12], Genetics (clinical), Exome sequencing, Loss function, Adaptor Proteins, Signal Transducing, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Learning Disabilities, Syndrome, Microdeletion syndrome, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hypotonia, Phenotype, 030104 developmental biology, Child, Preschool, Medical genetics, Drosophila, Female, medicine.symptom, Carrier Proteins, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.European Journal of Human Genetics advance online publication, 13 January 2016; doi:10.1038/ejhg.2015.282. ispartof: European Journal of Human Genetics vol:24 issue:8 pages:1145-1153 ispartof: location:England status: published

Published
2016

42. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Author

Jay Shendure, Jerrod J. Schwartz, Simon E. Fisher, Mark J. Rieder, Deborah A. Nickerson, Brian J. O'Roak, Pelagia Deriziotis, Emre Karakoc, Evan E. Eichler, Sarah B. Ng, Alexandra P. MacKenzie, Laura Vives, Raphael Bernier, Choli Lee, Carl Baker, and Santhosh Girirajan

Subjects
Proband, Adult, Male, Candidate gene, CNTNAP2, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Locus heterogeneity, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Child, Exome sequencing, 030304 developmental biology, 0303 health sciences, Mutation, Exons, Sequence Analysis, DNA, Middle Aged, medicine.disease, Pedigree, Developmental disorder, Child Development Disorders, Pervasive, Female, 030217 neurology & neurosurgery
Abstract

Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs. © 2011 Nature America, Inc. All rights reserved.

Published
2016

43. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author

Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Heterozygote, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Biology, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Order, Genetics, medicine, Humans, Copy-number variation, Clinical genetics, Obesity, Young adult, Child, Genetics (clinical), 030304 developmental biology, Child Development Disorders, Pervasive/diagnosis, Child Development Disorders, Pervasive/genetics, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities/diagnosis, Developmental Disabilities/genetics, Female, Intelligence Tests, Phenotype, Syndrome, 2. Zero hunger, Psychiatry, 0303 health sciences, Intelligence quotient, Neuropsychology, Complex traits, medicine.disease, Comorbidity, 3. Good health, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Medical genetics, Human medicine, Copy-Number Variation, 030217 neurology & neurosurgery
Abstract

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Published
2012

44. Evidence for Involvement of GNB1L in Autism

Author

Debby W. Tsuang, Zoran Brkanac, Nancy J. Minshew, Ellen M. Wijsman, Mark Lisowski, Geraldine Dawson, Wendy H. Raskind, Youngmee Sul, Evan E. Eichler, Deborah A. Nickerson, Gerard D Shellenberg, Santhosh Girirajan, Raphael Bernier, Ying-Zhang Chen, Annette Estes, Mark J. Rieder, Mark Matsushita, Ming T. Tsuang, and Elizabeth Sun

Subjects
Male, DNA Mutational Analysis, 22q11.2, translocation, Bioinformatics, Translocation, Genetic, 0302 clinical medicine, Gene Duplication, Gene duplication, Missense mutation, Heritability of autism, Child, Genetics (clinical), Research Articles, Genetics, 0303 health sciences, neurodevelopmental disorders, Intracellular Signaling Peptides and Proteins, Chromosome Breakage, 3. Good health, Pedigree, Psychiatry and Mental health, Child, Preschool, Female, Chromosome breakage, Haploinsufficiency, TBX1, Adolescent, DNA Copy Number Variations, Molecular Sequence Data, Non-allelic homologous recombination, Mutation, Missense, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, mental disorders, medicine, Humans, Family, Genetic Predisposition to Disease, Autistic Disorder, 030304 developmental biology, Base Sequence, Infant, Newborn, medicine.disease, Case-Control Studies, Karyotyping, Mutation, Autism, 030217 neurology & neurosurgery
Abstract

Structural variations in the chromosome 22q11.2 region mediated by nonallelic homologous recombination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders (ASDs). The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5 Mb region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism, and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization (CGH) we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy number evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (P = 0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in ASDs as well. © 2011 Wiley Periodicals, Inc.

Published
2011

45. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

Author

Raman Kumar, Eric Haan, Paolo Bosco, Bradley P. Coe, Marjolein H. Willemsen, Jozef Gecz, Cherie C Green, B. B. A. de Vries, B W M van Bon, Ingrid E. Scheffer, Francesca Cristofoli, J. Gerdts, Raphael Bernier, Deana Li, Marco Fichera, Kali Witherspoon, Corrado Romano, Evan E. Eichler, Tjitske Kleefstra, Heather C Mefford, Hilde Peeters, and David G. Amaral

Subjects
Adult, Male, 0301 basic medicine, Down syndrome, Microcephaly, Adolescent, Stereotypic Movement Disorder, Protein Serine-Threonine Kinases, Article, Seizures, Febrile, Speech Disorders, Cohort Studies, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Intellectual Disability, Intellectual disability, medicine, Humans, Autistic Disorder, Child, Molecular Biology, Genetics, Fetal Growth Retardation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Siblings, Syndrome, Middle Aged, Protein-Tyrosine Kinases, medicine.disease, Stereotypic movement disorder, Psychiatry and Mental health, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Mutation, Autism, Female, Haploinsufficiency, Psychology, Trisomy, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 167733.pdf (Publisher’s version ) (Closed access) Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 x 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

Published
2015

46. De novo TBR1 mutations in sporadic autism disrupt protein functions

Author

Jay Shendure, Jennifer Gerdts, Pelagia Deriziotis, Simon E. Fisher, Brian J. O'Roak, Danai Dimitropoulou, Sarah A. Graham, Evan E. Eichler, Sara Busquets Estruch, and Raphael Bernier

Subjects
Neuroinformatics, Male, genetic structures, Autism Spectrum Disorder, Molecular Sequence Data, Mutation, Missense, General Physics and Astronomy, medicine.disease_cause, behavioral disciplines and activities, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, Tumor, Two-Hybrid System Techniques, mental disorders, Protein Interaction Mapping, medicine, Missense mutation, Humans, Amino Acid Sequence, Child, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Genetics, Protein function, Mutation, Language Disorders, Multidisciplinary, biology, Sequence Homology, Amino Acid, HEK 293 cells, High-Throughput Nucleotide Sequencing, Forkhead Transcription Factors, General Chemistry, medicine.disease, HEK293 Cells, Autism spectrum disorder, Child, Preschool, biology.protein, Mutagenesis, Site-Directed, Autism, Female, TBR1, T-Box Domain Proteins, Dimerization
Abstract

Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

Published
2014

47. The Autism Simplex Collection : an international, expertly phenotyped autism sample for genetic and phenotypic analyses

Author

Louise Gallagher, James S. Sutcliffe, Fritz Poustka, Daniel H. Geschwind, Guiomar Oliveira, Dalila Pinto, Astrid M. Vicente, Sabine M. Klauck, Peter Szatmari, Raphael Bernier, Michael L. Cuccaro, Christine M. Freitag, Andy Shih, Veronica J. Vieland, Stephen W. Scherer, Jessica M. Brownfeld, Hilary Coon, Joseph D. Buxbaum, Joachim Hallmayer, Nadia Bolshakova, Patrick Bender, John I. Nurnberger, Edwin H. Cook, and Richard Anney

Subjects
medicine.medical_specialty, Autism, Clinical Sciences, Saúde Pública, Developmental Neuroscience, Peabody Picture Vocabulary Test, mental disorders, medicine, ddc:610, Psychiatry, Molecular Biology, Genotyping, Exome sequencing, Portugal, Research, Neurosciences, medicine.disease, Checklist, 3. Good health, SNP genotyping, Psychiatry and Mental health, Autism spectrum disorder, Perturbações do Desenvolvimento Infantil e Saúde Mental, Sample collection, Psychology, Developmental Biology
Abstract

Background: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. Methods: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Results: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). Conclusions: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.

Published
2014

48. Social attention: a possible early indicator of efficacy in autism clinical trials

Author

Robert H. Ring, Raphael Bernier, and Geraldine Dawson

Subjects
Autism, Cognitive Neuroscience, Review, Oxytocin, lcsh:RC321-571, Pathology and Forensic Medicine, Developmental psychology, Clinical trials, Social cognition, Intervention (counseling), medicine, Autism spectrum disorder, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neuropsychology, medicine.disease, Moderation, Social reward, Clinical trial, Behavioral intervention, Social attention, Pediatrics, Perinatology and Child Health, Neurology (clinical), Psychology, Construct (philosophy)
Abstract

For decades, researchers have sought to clarify the nature of the social communication impairments in autism, highlighting impaired or atypical 'social attention' as a key measurable construct that helps to define the core impairment of social communication. In this paper, we provide an overview of research on social attention impairments in autism and their relation to deficiencies in neural circuitry related to social reward. We offer a framework for considering social attention as a potential moderator or mediator of response to early behavioral intervention, and as an early indicator of efficacy of behavioral and/or pharmacological treatments aimed at addressing the social impairments in autism.

Published
2012
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49. Evidence for broader autism phenotype characteristics in parents from multiple incidence autism families

Author

Raphael Bernier, Geraldine Dawson, Jennifer Gerdts, Annette Estes, and Jeff Munson

Subjects
Adult, Male, Parents, Post hoc, Developmental Disabilities, behavioral disciplines and activities, Article, Developmental psychology, Genetic transmission, mental disorders, medicine, Humans, Autistic Disorder, Child, Social Behavior, Genetics (clinical), Analysis of Variance, General Neuroscience, Incidence (epidemiology), Incidence, Siblings, medicine.disease, Phenotype, Autism spectrum disorder, Autism, Female, Neurology (clinical), Analysis of variance, Psychology, Social motivation
Abstract

The broader autism phenotype was assessed in parents who have two or more children with ASD (multiplex autism), parents who have no more than one child with ASD (simplex autism), parents who have a child with developmental delay without ASD, and parents who have typically developing children. Clinicians, naive to parent group membership status, rated broader autism phenotype characteristics from videotaped administration of the Broader Autism Phenotype Symptom Scale (BPASS). Differences among groups in BPASS scores in the four assessed domains (social motivation, conversational skills, expressiveness, and restricted interests) were examined using multivariate ANOVA and post-hoc comparisons. Further, ratings of videotapes by observers naive to family status were compared to live, non-naïve ratings by observers who were aware of family status (non-naïve). Findings demonstrate that the BPASS is an instrument resistant to rater bias. Parents from multiplex autism families showed significantly more autism phenotype characteristics than the parents in the other groups. Moreover, the parents from simplex autism families did not differ from the parents of children with developmental delay or typical development. Finally, no differences between live, non-naive ratings and videotaped, naive ratings were observed. These findings suggest that characteristics of the broader autism phenotype, specifically in the social and communication domains, are present in multiplex autism parents to a greater degree than simplex autism and control parents. Further, the results provide support for the notion that genetic transmission mechanisms may differ between families with more than one child with autism and families with only one child with autism.

Published
2011

50. The Broader Autism Phenotype and Its Implications on the Etiology and Treatment of Autism Spectrum Disorders

Author

Jennifer Gerdts and Raphael Bernier

Subjects
medicine.medical_specialty, Mechanism (biology), business.industry, lcsh:RC435-571, Concordance, General Medicine, Review Article, medicine.disease, Phenotype, behavioral disciplines and activities, Autism spectrum disorder, lcsh:Psychiatry, mental disorders, medicine, Etiology, Autism, Heritability of autism, Communication skills, Psychiatry, business, Clinical psychology
Abstract

The presence of autism-related traits has been well documented in undiagnosed family members of individuals with autism spectrum disorder (ASD). The most common finding is mild impairments in social and communication skills that are similar to those shown by individuals with autism, but exhibited to a lesser degree. Termed thebroader autism phenotype(BAP), these traits suggest a genetic liability for autism-related traits in families. Genetic influence in autism is strong, with identical twins showing high concordance for the diagnosis and related traits and approximately 20% of all ASD cases having an identified genetic mechanism. This paper highlights the studies conducted to date regarding the BAP and considers the implications of these findings for the etiology and treatment of ASD.

Published
2011

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