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Mol Genet Genomic Med. 2016 Jul 30;4(5):568-80. doi: 10.1002/mgg3.235. eCollection 2016 Sep.

Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.

Author information

Department of Genetics UMC Utrecht Utrecht The Netherlands.
Tel Aviv Sourasky Medical Center6 Weizmann St.Tel AvivIsrael; Genetics of Epilepsy Research in Israel Tel-Aviv University Medical SchoolTel-AvivIsrael.
Neurogenetics GroupDepartment of Molecular GeneticsVIBAntwerpBelgium; Laboratory of NeurogeneticsInstitute Born-BungeUniversity of AntwerpAntwerpBelgium; Division of NeurologyAntwerp University HospitalAntwerpBelgium.
Neurogenetics GroupDepartment of Molecular GeneticsVIBAntwerpBelgium; Laboratory of NeurogeneticsInstitute Born-BungeUniversity of AntwerpAntwerpBelgium.
Neuroscience Department Children's Hospital Anna Meyer University of Florence Florence Italy.
Division of NeurologyThe Children's Hospital of PhiladelphiaPhiladephiaPennsylvania; Department of NeuropediatricsUniversity Medical Center Schleswig-HolsteinChristian Albrechts UniversityKielGermany.
Neurogenetics Group Department of Molecular Genetics VIB Antwerp Belgium.
Pediatric Epilepsy Unit Tel Aviv Sourasky Medical Center Tel Aviv University Tel Aviv Israel.
Department of Life Sciences Bethlehem University Bethlehem Palestine.
Folkhälsan Institute of Genetics Neuroscience Center and Research Programs Unit Molecular Neurology University of Helsinki Helsinki Finland.
Institute of Human Genetics University of Leipzig Hospitals and Clinics Leipzig Germany.
Danish Epilepsy Centre - FiladelfiaDianalundDenmark; Institute for Regional Health ServicesUniversity of Southern DenmarkDK-5230OdenseDenmark.
Department of Neuropediatrics University Medical Center Schleswig-Holstein Christian Albrechts University Kiel Germany.



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.


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.


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.


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.


De novo; HNRNPU; X‐linked; epileptic encephalopathy; loss‐of‐function; prioritization; recessive; targeted panel sequencing

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