Whole-exome sequencing to detect de novo genomic variation in motorstereotypies

     Whole exome-sequencing (WES) provides genetic sequence for all coding regions of the genome. Applying this approach to several neuropsychiatric disorders has yielded a better understanding of their genetic background... [ view full abstract ]

     Whole exome-sequencing (WES) provides genetic sequence for all coding regions of the genome. Applying this approach to several neuropsychiatric disorders has yielded a better understanding of their genetic background and underlying biology. To date, there are no published genetic studies of motor stereotypies (MS), a core phenotype of autism spectrum disorder (ASD) with uncertain biology. MS are repetitive, rhythmic, bilateral, movements with fixed patterns that can be socially impairing and in some cases self-injurious. In addition to their occurrence in ASD, MS can also occur in typically-developing children, offering the advantage of eliminating genetic heterogeneity associated with ASD. We performed WES in 118 parent-child trios, consisting of healthy parents and affected children in order to detect de novo mutations, arising spontaneously in the germline or fertilized egg. This approach has been fruitful in other neuropsychiatric disorders and is justified in MS, as 50% of cases cannot be attributed to familial risk (sporadic). A significant enrichment of damaging de novo mutations in cases versus 368 control trios suggests a contribution of this class of mutation to MS risk. Furthermore, two de novo loss of function (nonsense) mutations in the gene KDM5B were detected in two unrelated individuals, a recurrence highly unlikely to occur by chance. Both mutations lead to the rise of a premature stop codon, resulting in early truncation of the protein. Our study concludes that KDM5B is a high confidence risk gene for MS. The de novo nonsense mutations in KDM5B are likely to result in dysfunctional histone modification in affected children. These findings of recurrent de novo mutations in our patient cohort has the potential to lead to discovery of targeted therapeutics and is evidence of the potential of this sequencing approach for discovering more risk genes that will clarify disease biology.