Open AccessTargeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients
Author(s) -
Kovel Carolien G.F.,
Brilstra Eva H.,
Kempen Marjan J.A.,
Slot Ruben,
Nijman Isaac J.,
Afawi Zaid,
De Jonghe Peter,
Djémié Tania,
Guerrini Renzo,
Hardies Katia,
Helbig Ingo,
Hendrickx Rik,
Kanaan Moine,
Kramer Uri,
Lehesjoki AnnaElina E.,
Lemke Johannes R.,
Marini Carla,
Mei Davide,
Møller Rikke S.,
Pendziwiat Manuela,
Stamberger Hannah,
Suls Arvid,
Weckhuysen Sarah,
Koeleman Bobby P.C.
Publication year - 2016
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.235
Subject(s) - candidate gene , gene , genetics , frameshift mutation , phenotype , biology , loss function
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 EEF 1A2, KCNB 1 and the X‐linked gene IQSEC 2 . 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 HNRNPU mutations lead to severe developmental delay and febrile seizures in the first year of life.