Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.
Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.
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DOI：
10.1002/mgg3.235
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发表时间：
2016-09
影响因子：
2
通讯作者：
Koeleman, Bobby P. C.
中科院分区：
文献类型：
--
作者：
de Kovel, Carolien G. F.;Brilstra, Eva H.;van Kempen, Marjan J. A.;van't Slot, Ruben;Nijman, Isaac J.;Afawi, Zaid;De Jonghe, Peter;Djemie, Tania;Guerrini, Renzo;Hardies, Katia;Helbig, Ingo;Hendrickx, Rik;Kanaan, Moine;Kramer, Uri;Lehesjoki, Anna-Elina E.;Lemke, Johannes R.;Marini, Carla;Mei, Davide;Moller, Rikke S.;Pendziwiat, Manuela;Stamberger, Hannah;Suls, Arvid;Weckhuysen, Sarah;Koeleman, Bobby P. C.
关键词：
许多基因都是参与癫痫性脑病（EE）的候选基因，因为在患者中发现了一种或几种可能的致病变异，但没有足够的遗传或功能证据来进行明确的注释。为了增加经过验证的 EE 基因的数量，我们对 360 名患者的 26 个已知 EE 基因和 351 个候选 EE 基因进行了测序。对 41 名患者的 25 个已知与 EE 或相关表型有关的基因的变异进行了随访。我们对候选基因进行了优先排序，并跟踪了候选基因优先子集中的 31 个变异。 EE (19) 或相关疾病 (10) 的已知基因中的 29 个基因型（显性、隐性或 X 连锁）被归类为可能的致病变异。其中，在起主导作用的EE基因中发现了可能的致病性从头变异，包括最近发现的基因EEF1A2、KCNB1和X连锁基因IQSEC2。候选基因HNRNPU中的从头移码变异是随访候选基因中发现的唯一从头变异，患者的表型与最近发表的一些文章相似。 OMIM 中描述的基因突变（例如智力障碍基因）可能导致临床上被归类为 EE 的表型。我们证实了现有的文献报道，从头功能丧失的 HNRNPU 突变会导致生命第一年的严重发育迟缓和热性惊厥。
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.
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