de Kovel, CGF;
Brilstra, EH;
Van Kempen, MJA;
Van‘t Slot, R;
Nijman, IJ;
Afawi, Z;
De Jonghe, P;
... Koeleman, BPC; + view all
(2016)
Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.
Molecular Genetics and Genomic Medicine
, 4
(5)
pp. 568-580.
10.1002/mgg3.235.
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Abstract
Background Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation. Methods To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes. Results Twenty‐nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X‐linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X‐linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed‐up candidate genes, and the patient's phenotype was similar to a few recent publications. Conclusion Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss‐of‐function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life.
| Type: | Article |
|---|---|
| Title: | Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/mgg3.235 |
| Publisher version: | https://doi.org/10.1002/mgg3.235 |
| Language: | English |
| Additional information: | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | De novo, epileptic encephalopathy, HNRNPU, loss-of-function, prioritization, recessive, targeted panel sequencing, X-linked |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10073798 |
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