Function-based Variant Assessment of Epilepsome Genes to Increase Diagnostic Yield

Nemametrix, Inc., Eugene OR

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Abstract

1/5/2019 epilepsome phase 1 - Jan 5, 2019 - Google Docs Technical Summary Epilepsy is a significant health problem affecting 1% of the human population. Genome wide DNA sequencing, which is now being adopted in clinical practice, has led to the identification of an increasing number of variants a in epilepsy­associated genes. However, clinical interpretation of the new variants is challenging. Some of the variants are known to be either pathological or benign, yet a majority of gene variations have unknown functional consequence. Lack of functional annotation makes the growing number of Variants of Uncertain Significance (VUSes) being identified in genes for human diseases a significant barrier to making diagnoses and implementing therapies. Bioinformatic approaches can provide some insight into pathogenic potential of VUS alleles, but functional studies in animal model systems are needed to make definitive pathogenicity assignments. The expense and long timelines of mouse model production make the use of alternative animal models attractive. In this proposal, the C. elegans nematode is used as an alternative model capable of fast, high­throughput production and screening. Human genes can be installed as gene­swap replacements of the native disease­gene homologs decoupling the need for the residue to be conserved in worms. In prior work, gene­swap humanization of STXBP1 in the unc­18 locus rescued severe locomotion and behavior defects present in the gene KO animals. Similarly, gene­swap humanization of KCNQ2 also rescued loss of function and lead to activity restoration towards wildtype. Pathogenic variants introduced into the STXBP1 and KCNQ2 gene­swap loci lead to significant disruption of activity. In this proposal, the system is expanded to address a large set of VUSes from 8 more epilepsy­associated genes covering more than 50% of the known monogenic causes of epilepsy. The result is a set of animal models for capturing the biology of novel variants and increasing diagnostic yield of clinical genomic testing. https://docs.google.com/document/d/1RoyJns09p8TOCWmPbVtFoYWm2i9khfE3w_UihlNNL-o/edit#heading=h.hx89obtutlfb 2/14