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.
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Funding This work was supported by funding from the Canadian Institutes for Health Research (CIHR) (RT-64217; PI: MESL), Autism Speaks (PI: MESL), Michael Smith Foundation for Health Research (PI: MESL) a CIHR Interdisciplinary Health Research Team grant (RT-43820) to ASD-CARC (PI: JJAH) [http://www.AutismResearch.com], and the Ontario Mental Health Foundation (PI: JJAH). YQ, NR and MK are trainees with the CIHR/NAAR-Autism Speaks STIHR Inter-Institute Autism Spectrum Disorders Training Program (PI: JJAH). ERS is supported by a CIHR Institute of Genetics Clinician Investigator Award (2005–09). MESL and ERS are Career Scholars supported by the Michael Smith Foundation for Health Research.
Competing interests None.
Patient consent Not required.
Provenance and peer review Commissioned; externally peer reviewed.
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