Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.
Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.
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DOI：
10.1002/ana.25243
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发表时间：
2018-06
影响因子：
11.2
通讯作者：
Heinzen EL
中科院分区：
文献类型：
--
作者：
Winawer MR;Griffin NG;Samanamud J;Baugh EH;Rathakrishnan D;Ramalingam S;Zagzag D;Schevon CA;Dugan P;Hegde M;Sheth SA;McKhann GM;Doyle WK;Grant GA;Porter BE;Mikati MA;Muh CR;Malone CD;Bergin AMR;Peters JM;McBrian DK;Pack AM;Akman CI;LaCoursiere CM;Keever KM;Madsen JR;Yang E;Lidov HGW;Shain C;Allen AS;Canoll PD;Crino PB;Poduri AH;Heinzen EL
体细胞变异是癫痫相关的局灶性皮质发育畸形（MCD）的公认原因。我们假设体细胞变异可能是更广泛的局灶性癫痫的基础，包括非病变局灶性癫痫（NLFE）。通过对脑组织的遗传分析，我们评估了躯体变异在伴和不伴MCD的局灶性癫痫中的作用。我们通过对18例NLFE患者和38例局灶性MCD患者的癫痫手术标本和白细胞进行高深度外显子组和超高深度候选基因测序，确定了体细胞变异。我们在5例SLC35A2患者中观察到体细胞变异，SLC35A2基因与糖基化缺陷和罕见的x连锁癫痫性脑病相关。SLC35A2非同义变异在NLFE患者（1女2男）的3/18（17%）脑中检测到，且在白细胞中缺失，脑源DNA变异等位基因频率（VAFs）为2-14%。病理评估显示局灶性皮质发育不良Ia型（FCD1a）在三个NLFE病例中的两个。在MCD队列中，在两名患有顽固性癫痫、发育迟缓和MRI提示FCD的男性患者的大脑中检测到SCL35A2的非同义变异，VAFs为19-53%；在脑组织标本中均未观察到FCD的证据。我们报道SLC35A2的体细胞变异可以解释NLFE的很大一部分，这是一种很大程度上无法解释的疾病，以及局灶性MCD，以前被证明是由体细胞突变引起的，但直到现在只在PI3K-AKT-mTOR途径基因中。总的来说，我们的研究结果表明，在顽固性癫痫中，糖基化缺陷的作用比以前认识到的更大。
Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including non-lesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. We observed somatic variants in five cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3/18 individuals (17%) with NLFE, one female and two males, with variant allele frequencies (VAFs) in brain-derived DNA of 2–14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in two of the three NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of two males with intractable epilepsy, developmental delay, and MRI suggesting FCD, with VAFs of 19–53%; evidence for FCD was not observed in either brain tissue specimen. We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies.
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影响因子：
30.8
作者：
Carvill, Gemma L.;Regan, Brigid M.;Yendle, Simone C.;O'Roak, Brian J.;Lozovaya, Natalia;Bruneau, Nadine;Burnashev, Nail;Khan, Adiba;Cook, Joseph;Geraghty, Eileen;Sadleir, Lynette G.;Turner, Samantha J.;Tsai, Meng-Han;Webster, Richard;Ouvrier, Robert;Damiano, John A.;Berkovic, Samuel F.;Shendure, Jay;Hildebrand, Michael S.;Szepetowski, Pierre;Scheffer, Ingrid E.;Mefford, Heather C.
通讯作者：
Mefford, Heather C.
影响因子：
9.8
作者：
Dazzo, Emanuela;Fanciulli, Manuela;Nobile, Carlo
通讯作者：
Nobile, Carlo
影响因子：
9.9
作者：
Hesdorffer, D. C.;Logroscino, G.;Hauser, W. A.
通讯作者：
Hauser, W. A.
影响因子：
14.9
作者：
Costello M;Pugh TJ;Fennell TJ;Stewart C;Lichtenstein L;Meldrim JC;Fostel JL;Friedrich DC;Perrin D;Dionne D;Kim S;Gabriel SB;Lander ES;Fisher S;Getz G
通讯作者：
Getz G
影响因子：
4.2
作者：
Doerre, K.;Olczak, M.;Marquardt, T.
通讯作者：
Marquardt, T.