Autism spectrum disorder (ASD) is a clinically and etiologically heterogeneous condition with high prevalence amongst all world populations. Due to the life long morbidity, ASD poses a profound world-wide public health challenge. Despite its obviously high heritability, a genetic cause is only identified in a small fraction of patients due to its complex etiologic heterogeneity. Recently, whole genome sequencing (WGS) emerged as a powerful tool for variant discovery due to its comprehensive and uniform coverage and is expected to be beneficial for studying ASD. We used WGS to examine 20 families with ASD, mainly from Qatar, as well as from a few other Arabic countries, to detect de novo or rare inherited genetic variants predicted to be of pathogenic significance. All probands were diagnosed with ASD by at least an ADI-R (Autism Diagnostic Interview-revised) evaluation, in addition to other screening or confirmatory tools and were recruited from the Shafallah Center for Children with Special Needs. Due to the nature of the ascertainment source, all probands had associated intellectual impairment. In all probands known causes of ASD were excluded, fragile X syndrome by PCR and Southern blott, Rett syndrome (for females) by Sanger resequencing and MLPA and Copy Number Variations (CNV) by SNP genotyping on an Illumina 1M-Duo SNP chips. Among all probands, we identified deleterious de novo mutations in six (30%) families and inherited X-linked in two families (10%). We did not identify any inherited autosomal dominant mutations, but identified putative inherited autosomal recessive varations in three families (15%). The deleterious de novo variants were found in five previously unrecognized autosomal genes, and in one known autosomal ASD gene. The inherted X-linked variations were found in ASD risk genes. We are interested in deeper examination of the putative variations with autosomal recessive pattern of inheritance, since the parents of 60% of the probands are consanguineous. The deeper examination will employ the study of knock-out and knock-in mouse models and different in silico and in vitro protein modeling studies. These results so far suggest that WGS of a trio coupled with thorough bioinformatic analyses provide a powerful diagnostic tool in ASD. It is also a potent methodology for gene discovery in ASD, which may provide the basis for genetic testing for early diagnosis and early targeted intervention with a final goal of better outcome.


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