دورية أكاديمية
Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A.
| العنوان: | Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A. |
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| المؤلفون: | 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, Guigo, Roderic, Petryszak, Robert, Minassian, Berge A., Cavalleri, Gianpiero, Vitsios, Dimitrios, Petrovski, Slave, Harrow, Jennifer, Flicek, Paul, Lucy Raymond, F., Lench, Nicholas J., Jonghe, Peter De, Mudge, Jonathan M., Weckhuysen, Sarah, Sisodiya, Sanjay M., Frankish, Adam |
| المصدر: | npj Genomic Medicine, 4, 31 (2019-12-02) |
| بيانات النشر: | Nature Publishing Group, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Medical genomics, Molecular medicine, Human health sciences, Pediatrics, Neurology, Sciences de la santé humaine, Pédiatrie, Neurologie |
| الوصف: | 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. |
| نوع الوثيقة: | journal article http://purl.org/coar/resource_type/c_6501 article |
| اللغة: | English |
| Relation: | urn:issn:2056-7944 |
| DOI: | 10.1038/s41525-019-0106-7 |
| URL الوصول: | https://orbi.uliege.be/handle/2268/244273 |
| حقوق: | open access http://purl.org/coar/access_right/c_abf2 info:eu-repo/semantics/openAccess |
| رقم الأكسشن: | edsorb.244273 |
| قاعدة البيانات: | ORBi |
| DOI: | 10.1038/s41525-019-0106-7 |
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