Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in .

Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in .

Steward, Charles A;Roovers, Jolien;Suner, Marie-Marthe;Gonzalez, Jose M;Uszczynska-Ratajczak, Barbara;Pervouchine, Dmitri;Fitzgerald, Stephen;Viola, Margarida;Stamberger, Hannah;Hamdan, Fadi F;Ceulemans, Berten;Leroy, Patricia;Nava, Caroline;Lepine, Anne;Tapanari, Electra;Keiller, Don;Abbs, Stephen;Sanchis-Juan, Alba;Grozeva, Detelina;Rogers, Anthony S;Diekhans, Mark;Guigó, Roderic;Petryszak, Robert;Minassian, Berge A;Cavalleri, Gianpiero;Vitsios, Dimitrios;Petrovski, Slavé;Harrow, Jennifer;Flicek, Paul;Lucy Raymond, F;Lench, Nicholas J;Jonghe, Peter De;Mudge, Jonathan M;Weckhuysen, Sarah;Sisodiya, Sanjay M;Frankish, Adam;
npj genomic medicine 2019 Vol. 4 pp. 31
241
steward2019reannotationnpj

Abstract

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.

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