Phenomic determinants of genomic variation in autism spectrum disorders

• Published in: Journal of medical genetics Vol. 46; no. 10; pp. 680 - 688
• Main Authors: Qiao, Y, Riendeau, N, Koochek, M, Liu, X, Harvard, Chansonette, Hildebrand, M J, Holden, J J A, Rajcan-Separovic, E, Lewis, M E S
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.10.2009; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Adolescent; Adult; Artificial chromosomes; Autism; Biological and medical sciences; Child; Child clinical studies; Child Development Disorders, Pervasive - genetics; Child, Preschool; Cohort Studies; Developmental disorders; Female; Females; Fundamental and applied biological sciences. Psychology; Gene Dosage; General aspects. Genetic counseling; Genes; Genetic disorders; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Genotype; Genotype & phenotype; Humans; Infantile autism; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Phenotype; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Software; United States > US; California; Human; Variations; Autism; Genetics; Pervasive developmental disorder; Developmental disorder
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2009.066795

Background:Autism spectrum disorders (ASDs) are common, heritable neurobiologic conditions of unknown aetiology confounded by significant clinical and genetic heterogeneity.Methods:This study evaluated a broad categorisation of phenotypic traits (or phenome) for 100 subjects with Autism Diagnostic Interview-Revised/Autism Diagnostic Observation Schedule-Generic (ADI-R/ADOS-G) confirmed idiopathic ASD undergoing 1 Mb bacterial artificial chromosome (BAC) array comparative genomic hybridisation (CGH).Results and conclusions:Array CGH uncovered nine different pathogenic copy number variants (pCNVs) in 9/100 ASD subjects having complex phenotypes (ASD± intellectual disability (ID; IQ<70)) and/or physical anomalies), normal karyotype, fragile X analysis, and comprehensive evaluation by a clinical geneticist. Unique pCNVs in our cohort included del(5)(p15.2p15.31) (2.4 Mb), del(3)(p24.3) (0.1 Mb) and dup(18)(p11.3)(0.9 Mb). Five pCNVs were recurrent in our cohort or were previously described in subjects with ASD±ID: (dup(7)(q11.23)(1.5 Mb); del(2)(p15p16.1) (6.1 Mb and 7.9 Mb); del(14)(q11.2) (0.7 Mb) and dup(15)(q11q13) (10 Mb), including del(X)(p11.22) (470 Kb) in two autistic brothers. Male: female distribution in subjects with pCNVs was reduced to 1.25:1 from 3.2:1 in the original cohort. The authors stratified the study population according to a broad spectrum of clinical features and correlated specific phenotypes with respect to CNV load and pathogenicity. The findings indicate increased prevalence of pCNVs in subjects with microcephaly (<2nd centile; n = 2 of 4 ASD subjects with microcephaly; p = 0.04), and ID (n = 9 of 64 subjects with ASD and ID; p = 0.02). Interestingly, in the absence of ID co-morbidity with an ASD, no pCNVs were found. The relationship between parental ages at delivery and CNV load and pathogenicity was also explored.