Abstracts

Rationale: Developmental and epileptic encephalopathies (DEEs) are a group of severe, early onset epilepsies characterized by refractory seizures, frequent epileptiform activity, developmental delay and/or regression, and often a poor prognosis. DEEs are highly genetically heterogeneous with over 60 genes implicated. Despite significant progress, about half of the DEEs remain unexplained with current clinical diagnostic testing.We sought to identify novel genetic causes of DEEs through whole exome sequencing. Methods: Whole exome sequencing was performed in 168 proband-parents trios, 21 proband-parent duos, and 25 proband only singletons. All probands were negative on screening for pathogenic variants in 58 known DEE genes. We prioritized ultra-rare, nonsynonymous variants for review. We explored various modes of inheritance including de novo (constitutive and somatic mosaic), compound heterozygous, newly homozygous, and X-linked hemizygous. Results: We identified pathogenic or likely pathogenic variants in 36/214 probands providing a molecular diagnosis for 16.8% of our unsolved cohort. Pathogenic de novo variants in known DEE genes were identified in 13/36 (36%) cases. These variants were missed in previous screening attempts due to insufficient coverage at the variant site or undetected mosaicism of the variant in the proband or his/her parent. Biallelic pathogenic variants were identified in 11/36 (31%) solved cases – a higher than expected occurrence of recessive inheritance in a cohort of apparently sporadic DEE.  Finally, we identified pathogenic de novo variants in genes associated with related neurodevelopmental disorders including intellectual disability and autism, in 12/36 (33%) solved cases. In addition, we identified de novo variants of uncertain significance in 110 genes not previously linked to DEE or other neurological disorder. De novo variants in the same candidate gene were not identified in multiple cases. We are currently performing targeted sequencing of 55 of these candidate genes in a cohort of ~750 unsolved DEE patients to identify additional cases. We have identified additional de novo variants in 4 genes: CMPK2, CPSF1, IRF2BPL and KCNV2. Conclusions: Exome sequencing in 214 DEE cases identifies novel candidate DEE genes, implicates novel pathways, and confirms the genetic heterogeneity of this group of disorders. Funding: AES Postdoctoral Research FellowshipNIH R01 NS069605