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Sub-microscopic chromosomal imbalances in idiopathic autism spectrum disorder (ASD) Koochek, Maryam


Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions characterized by clinical variability, genetic heterogeneity and a male to female ratio of 4:1. The frequency of the disorders is approximately 1/150 (US Centre for Disease Control) and heritability in idiopathic autism is estimated at over 90%. Several genome wide linkage analyses support the hypothesis of complex inheritance with involvement of many genes of small effect. Further, numerical and structural chromosomal anomalies involving almost all of the chromosomes have been previously reported. One class of chromosomal abnormalities that may have a significant involvement in the aetiology of ASDs include sub-microscopic genomic deletions and duplications also known as DNA Copy Number Variations (CNV). In this study, nineteen probands with a confirmed diagnosis of nonsyndromic ASD and additional complex phenotypic features (dysmorphisms +/- intellectual disability (ID)) with normal karyotype/Fragile X screening were evaluated for submicroscopic genomic imbalances using a commercially available 1Mb BAC microarray platform (Spectral Genomics). Additionally, two probands with a confirmed diagnosis of ASD and a previously identified chromosomal abnormality were used as positive controls. Probands from three families were determined to have a pathogenic or potentially pathogenic CNV following confirmation of their array findings by a secondary independent method such as FISH and/or qPCR. In the first multiplex (MPX), multigenerational family two probands had array profiles which suggested a gain of proximal 15q11-13, loss of 14q11 and gain of 6q22. Extensive FISH analysis for these probands and their relatives revealed a balanced cryptic translocation t(14;15)(q11.2;q13.3) segregating within the maternal lineage that was expressed in an unbalanced form in the affected individuals. In two other families, the probands had single clone gains at 18p11 .3 (de novo) and 21 q22.12 (maternal) respectively. Overall 3/19 (16%) of families with ASD probands with a normal karyotype were found to harbour an autism-specific CNV or cryptic chromosomal rearrangement that plays a pathogenic or potentially pathogenic role in the aetiology of ASD.

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