[en] 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 SCN1A 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 SCN1A 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 SCN1A 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.
Disciplines :
Neurology Pediatrics
Author, co-author :
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 ; Centre Hospitalier Universitaire de Liège - CHU > Département de Pédiatrie > Service de pédiatrie
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