期刊
NPJ GENOMIC MEDICINE
卷 4, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41525-019-0106-7
关键词
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资金
- National Human Genome Research Institute (NHGRI) [2U41HG007234]
- Wellcome Trust [WT108749/Z/15/Z]
- European Molecular Biology Laboratory
- Department of Health's NIHR Biomedical Research Centres funding scheme
- Epilepsy Society
- Agency for Innovation by Science and Technology, IWT
- Science Foundation Ireland (SFI)
- European Regional Development Fund [16/RC/3948]
- BOF-University of Antwerp [FFB180053]
- FWO [1861419N]
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.
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