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Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

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Steward, Charles A.  ORCID logo
Roovers, Jolien 
Suner, Marie-Marthe  ORCID logo
Gonzalez, Jose M. 
Uszczynska-Ratajczak, Barbara  ORCID logo


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 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.


Funder: Agency for Innovation by Science and Technology, IWT

Funder: U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)

Funder: BOF-University of Antwerp (FFB180053) and FWO (1861419N).


Article, /692/4017, /631/61/212/2301, article

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npj Genomic Medicine

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Nature Publishing Group UK
U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) (2U41HG007234, 2U41HG007234, 2U41HG007234, 2U41HG007234, 2U41HG007234, 2U41HG007234, 2U41HG007234, 2U41HG007234)
Wellcome Trust (Wellcome) (WT108749/Z/15/Z, WT108749/Z/15/Z, WT108749/Z/15/Z, WT108749/Z/15/Z, WT108749/Z/15/Z, WT108749/Z/15/Z, WT108749/Z/15/Z)