Abstracts

Rationale: The HudsonAlpha CSER Study is a translational study of the utility of whole exome/genome sequencing for identifying a genetic cause in children or adults with intellectual disability. To date we have enrolled 338 families, with sequencing and analysis complete for 307 families. The overall diagnostic rate for the CSER project is comparable to other studies. About 41% of patients receive a variant of interest (either pathogenic, likely pathogenic or a Variant of Uncertain Significance VUS), while about 59% of patients receive no primary diagnosis. Recently, a variety of somatic and germline mutations have been identified in genes involved in the mTOR pathway (including AKT3, PIK3R2, PIK3CA, and mTOR), which are associated with Focal Cortical Dysplasia (FCD), and hemimegalencephaly (HME). The mTOR pathway is critical for regulating protein synthesis, cell growth and regulation of nutritional status of the cell. We have identified 6 subjects with mTOR mutations which explain their clinical phenotype, including autism, intellectual disability and intractable epilepsy. Methods: Whole exome or genome sequencing has been conducted in patients exhibiting developmental delay and/or intellectual disability. All individuals were sequenced to an average depth of 65X (exome) or 30X (genome), with at least 80% of bases covered at 20X. After alignment to the reference genome, variants, locations where proband's sequence differs from that of the reference were annotated (e.g. population frequency, conservation, consequence to protein, prediction of deleteriousness, presence within/absence from disease databases, etc.) and filtered to identify potentially causative genetic variation. Through manual curation, variant annotations were integrated with information reported in the literature and variant pathogenicity was defined. Variants were carefully reviewed by a variant review committee composed of research geneticists and analysts, medical geneticists, a pediatric neurologist, and genetic counselors. Variants deemed to be causative, or potentially causative, were returned to patient families following Sanger confirmation in an independent laboratory. Results: (Table 1)-We have identified four subjects with germline de novo mutations and a set of half-siblings (subjects 5&6) with a likely maternally-inherited allele in mTOR using whole genome sequencing. All of the subjects have moderate/severe intellectual disability (ID) and 4/6 have been diagnosed with autism. Four of the six subjects have intractable epilepsy of which 2/6 have brain band heterotopia evident on MRIs, where the three remaining subjects showed evidence of ventricular enlargement and macrocephaly on MRI. Conclusions: The identification of protein-altering mTOR mutations in this group of patients builds on the growing evidence for the contribution of genes in the mTOR pathway to the development of intellectual disability, autism and epilepsy. It also highlights the value of genome sequencing for diagnosis and opens the possibilities for therapies with modulators of the mTOR pathway. Funding: NIH CSER Project-UM1-HG007301