TY - JOUR
T1 - Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients
AU - EuroEPINOMICS RES Consortium
AU - de Kovel, Carolien G.F.
AU - Brilstra, Eva H.
AU - Van Kempen, Marjan J.A.
AU - Van‘t Slot, Ruben
AU - Nijman, Isaac J.
AU - Afawi, Zaid
AU - De Jonghe, Peter
AU - Djémié, Tania
AU - Guerrini, Renzo
AU - Hardies, Katia
AU - Helbig, Ingo
AU - Hendrickx, Rik
AU - Kanaan, Moine
AU - Kramer, Uri
AU - Lehesjoki, Anna Elina E.
AU - Lemke, Johannes R.
AU - Marini, Carla
AU - Mei, Davide
AU - Møller, Rikke S.
AU - Pendziwiat, Manuela
AU - Stamberger, Hannah
AU - Suls, Arvid
AU - Weckhuysen, Sarah
AU - Balling, R.
AU - Barisic, N.
AU - Baulac, S.
AU - Caglayan, H. S.
AU - Craiu, D. C.
AU - Depienne, C.
AU - Gormley, P.
AU - Hjalgrim, H.
AU - Hoffman-Zacharska, D.
AU - Jähn, J.
AU - Klein, K. M.
AU - Komarek, V.
AU - LeGuern, E.
AU - Lerche, H.
AU - May, P.
AU - Muhle, H.
AU - Pal, D.
AU - Palotie, A.
AU - Rosenow, F.
AU - Selmer, K.
AU - Serratosa, J. M.
AU - Sisodiya, S. M.
AU - Stephani, U.
AU - Sterbova, K.
AU - Striano, P.
AU - Talvik, T.
AU - van Haelst, M.
AU - van't Slot, Ruben
AU - Koeleman, Bobby P. C.
AU - AUTHOR GROUP
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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 followedup 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.
AB - 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 followedup 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.
KW - De novo
KW - HNRNPU
KW - X-linked
KW - epileptic encephalopathy
KW - loss-of-function
KW - prioritization
KW - recessive
KW - targeted panel sequencing
UR - http://www.scopus.com/inward/record.url?scp=85015718168&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/mgg3.235
DO - https://doi.org/10.1002/mgg3.235
M3 - Article
C2 - 27652284
SN - 2324-9269
VL - 4
SP - 568
EP - 580
JO - Molecular genetics and genomic medicine
JF - Molecular genetics and genomic medicine
IS - 5
ER -