ABSTRACT
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
Subject(s)
Autistic Disorder/diagnosis , Autistic Disorder/genetics , Exome/genetics , Genome-Wide Association Study/methods , Adolescent , Animals , Cells, Cultured , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Pedigree , Rats , Sequence Analysis, DNA/methods , Young AdultABSTRACT
OBJECTIVE: To describe cognitive and behavioral features of patients with chromosome 16p11.2 deletion syndrome, a recently identified and common genetic cause of neurodevelopmental disability, especially autism spectrum disorder (ASD). METHOD: Twenty-one patients with 16p11.2 deletion were evaluated by medical record review. A subset of 11 patients consented to detailed cognitive, behavioral, and autism diagnostic assessment. RESULTS: Patients with 16p11.2 deletion had varying levels of intellectual disability, variable adaptive skills, and a high incidence of language delay. Attention issues were not as frequent as had been reported in previous clinical reports. Atypical language, reduced social skills, and maladaptive behaviors were common, as was diagnosis of ASD. Based on medical record review, 7 of 21 patients (33%) had an ASD diagnosis. Among patients receiving detailed phenotyping, 3 of 11 (27%) met full criteria (met cutoff scores on both Autism Diagnostic Observation Schedule and Autism Diagnostic Interview) for an ASD diagnosis, whereas 6 other patients (55%) met criteria for ASD on either the Autism Diagnostic Observation Schedule or the Autism Diagnostic Interview, but not both measures. CONCLUSIONS: Rates of ASD were similar to previous reports that are based on medical record reviews, but formal assessment revealed that a majority of patients with 16p11.2 deletion demonstrate features of ASD beyond simple language impairment. All patients with 16p11.2 deletion should receive formal neurodevelopmental evaluation including measures to specifically assess cognitive, adaptive, language, and psychiatric/behavioral issues. Clinical evaluation of this patient population should always include assessment by Autism Diagnostic Interview and Autism Diagnostic Observation Schedule to detect behaviors related to ASD and possible ASD diagnosis.
Subject(s)
Child Development Disorders, Pervasive/genetics , Chromosome Deletion , Chromosomes, Human, Pair 16/genetics , Intellectual Disability/genetics , Language Development Disorders/genetics , Adaptation, Psychological , Adolescent , Autistic Disorder/genetics , Boston/epidemiology , Child , Child Development Disorders, Pervasive/diagnosis , Child Development Disorders, Pervasive/epidemiology , Child Development Disorders, Pervasive/psychology , Child, Preschool , Female , Humans , Intellectual Disability/epidemiology , Intellectual Disability/psychology , Language Development Disorders/epidemiology , Language Development Disorders/psychology , Male , Medical Records/statistics & numerical data , Phenotype , Severity of Illness Index , Social Behavior , SyndromeABSTRACT
Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 x 10(-7)). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.
