Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome
Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome
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DOI：
10.1111/cge.12636
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发表时间：
2016-02-01
影响因子：
3.5
通讯作者：
Lesca, G.
中科院分区：
文献类型：
--
作者：
Dimassi, S.;Labalme, A.;Lesca, G.
婴儿痉挛综合征 (IS) 的特征是临床痉挛并伴有发作性电沉积，通常发生在 1 岁之前，并且经常与认知障碍相关。病因多种多样，40% 的患者病因仍难以捉摸。我们使用全外显子组测序 (WES) 搜索了 10 名 IS 先证者及其父母的从头突变。患者既无近亲关系，也无癫痫家族史。通过脑磁共振成像 (MRI)、代谢筛查、阵列比较基因组杂交 (CGH) 以及 CDKL5、STXBP1 突变和 ARX 重复检测，排除了 IS 的常见原因。我们在四名患者中发现了可能的致病突变。在两名 IS 发病前没有癫痫病史的患者中发现了 SCN2A (p.Leu1342Pro) 和 KCNQ2 (p.Ala306Thr) 的错义突变。之前曾在四名患有 IS 的女性中报道过 ALG13 的 p.Asn107Ser 错义突变。第四个突变是 NR2F1 中的框内缺失 (p.Phe110del)，该基因的突变会导致智力障碍、癫痫和视神经萎缩。此外，我们在 KIF3C 中发现了一个可能致病的变异，它编码在神经发育过程中表达的驱动蛋白。我们的结果证实，WES 显着提高了散发性 IS 患者的诊断率。
Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.