Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities

There is strong evidence for rare, highly penetrant genetic variants playing an etiological role in multiple neurodevelopmental disabilities, including autism spectrum disorders. The rate of discovery of such rare variants is increasing with the advent of larger sample collections, chromosome microarray analyses, and high-throughput sequencing. As the variants that are being discovered can be highly penetrant, they lead immediately to model systems with construct validity, critical for understanding the underlying neurobiology of these conditions, which in turn can provide leads for novel therapeutic targets. Moreover, these discoveries can benefit families with information about recurrence risk, resolve concerns about etiology, provide information about associated medical issues, and engender directed advocacy for specific genetic conditions. For these reasons, diagnostic laboratories are taking advantage of research data as they are produced. In the current report, we present our molecular analysis of a child with a purported disruptive mutation in SHANK3 identified by a commercial genetic testing laboratory and we provide evidence that this was not an etiological variant. The variant was a 1-bp insertion in exon 11 of the RefSeq gene, which we then determined was inherited from a healthy mother and found in ~1% of controls. Since the variant would be predicted to disrupt the reference gene, and the penetrance of SHANK3 mutations is very high, we did follow up molecular and bioinformatic analyses and concluded that the presumptive exon containing the variant is not likely to be present in most or all SHANK3 transcripts. The results highlight difficulties that can arise with rapid translation of research findings to clinical practice. Researchers are in a unique position to generate resources with collated and curated information that can inform research, genetic testing, clinicians, and families about the best practices as pertains to rare genetic variants in neurodevelopmental disabilities. Of immediate importance would be a well-curated database of gene variation identified in large numbers of typically developing individuals and in individuals affected with neurodevelopmental disabilities. Such a database would reduce false-positive results in clinical settings, would be helpful in structure-function analyses, and would direct translational research to pathways most likely to benefit families.