| Summary: | 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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