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

epilepsome phaseJanGoogle Docs Technical Summary Epilepsy is a significant health problem affectingof the human populationGenome wide DNA sequencingwhich is now being adopted in clinical practicehas led to the identification of an increasing number of variants a in epilepsy associated genesHoweverclinical interpretation of the new variants is challengingSome of the variants are known to be either pathological or benignyet a majority of gene variations have unknown functional consequenceLack of functional annotation makes the growing number of Variants of Uncertain SignificanceVUSesbeing identified in genes for human diseases a significant barrier to making diagnoses and implementing therapiesBioinformatic approaches can provide some insight into pathogenic potential of VUS allelesbut functional studies in animal model systems are needed to make definitive pathogenicity assignmentsThe expense and long timelines of mouse model production make the use of alternative animal models attractiveIn this proposalthe Celegans nematode is used as an alternative model capable of fasthigh throughput production and screeningHuman genes can be installed as gene swap replacements of the native disease gene homologs decoupling the need for the residue to be conserved in wormsIn prior workgene swap humanization of STXBPin the unclocus rescued severe locomotion and behavior defects present in the gene KO animalsSimilarlygene swap humanization of KCNQalso rescued loss of function and lead to activity restoration towards wildtypePathogenic variants introduced into the STXBPand KCNQgene swap loci lead to significant disruption of activityIn this proposalthe system is expanded to address a large set of VUSes frommore epilepsy associated genes covering more thanof the known monogenic causes of epilepsyThe result is a set of animal models for capturing the biology of novel variants and increasing diagnostic yield of clinical genomic testinghttpsdocs google com document dRoyJnsp TOCWmPbVtFoYWm i khfE w UihlNNL o edit heading h hxobtutlfbepilepsome phaseJanGoogle Docs Narrative Many cases of Epilepsy have genetic underpinings and doctors need to understand which of the genomic defects cause diseaseIn this projectsmall animal models are humanized to express defective genes associated with epilepsyThe resulting humanized animal models and their analysis will be used in understanding of disease mechanisms and ultimately discover new therapeuticshttpsdocs google com document dRoyJnsp TOCWmPbVtFoYWm i khfE w UihlNNL o edit