Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.
Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.
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DOI：
10.1093/hmg/ddu030
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发表时间：
2014-06-15
影响因子：
3.5
通讯作者：
Taylor JC
中科院分区：
文献类型：
--
作者：
Martin HC;Kim GE;Pagnamenta AT;Murakami Y;Carvill GL;Meyer E;Copley RR;Rimmer A;Barcia G;Fleming MR;Kronengold J;Brown MR;Hudspith KA;Broxholme J;Kanapin A;Cazier JB;Kinoshita T;Nabbout R;WGS500 Consortium;Bentley D;McVean G;Heavin S;Zaiwalla Z;McShane T;Mefford HC;Shears D;Stewart H;Kurian MA;Scheffer IE;Blair E;Donnelly P;Kaczmarek LK;Taylor JC
在严重的早发性癫痫中，精确的临床和分子遗传学诊断很复杂，因为许多代谢和电生理过程与疾病病因有关。临床表型具有许多共同特征，例如复杂的癫痫类型和发育迟缓。分子诊断历来仅限于对已知与特定亚表型相关的候选基因进行顺序测试，但这种方法的诊断率可能较低。我们对六名此前分子诊断难治的严重早发性癫痫患者及其父母进行了全基因组测序（WGS）。其中四名患者临床诊断为大田原综合征（OS），两名患者患有严重的非综合征性早发性癫痫（NSEOE）。在两个 OS 病例中，我们发现 KCNQ2 和 SCN2A 基因中存在从头非同义突变。在第三个 OS 病例中，全基因组测序揭示了 9 号染色体的父系二倍体，导致鉴定出 KCNT1 中的因果纯合错义变异，该变异导致钾通道电流大幅增加。第四名 OS 患者的 PIGQ 存在隐性突变，导致外显子跳跃和糖磷脂酰肌醇生物合成缺陷。两名 NSEOE 患者的 CBL 和 CSNK1G1 可能分别具有致病性新生突变。在另外 500 名癫痫患者中未发现这些基因突变。这项工作揭示了 OS 的两个新基因：KCNT1 和 PIGQ。它还揭示了意想不到的遗传机制，并强调了全基因组测序作为进行分子诊断的临床工具的力量，特别是对于高度异质性的疾病。
In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.
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影响因子：
4.8
作者：
Hong, Y;Ohishi, K;Kinoshita, T
通讯作者：
Kinoshita, T
DOI：
10.1534/g3.113.006130
发表时间：
2013-08-07
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Howlett IC;Rusan ZM;Parker L;Tanouye MA
通讯作者：
Tanouye MA
影响因子：
5.6
作者：
Berg, Anne T.;Berkovic, Samuel F.;Scheffer, Ingrid E.
通讯作者：
Scheffer, Ingrid E.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.5
作者：
Bhattacharjee, A;Gan, L;Kaczmarek, LK
通讯作者：
Kaczmarek, LK