Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis.
Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis.
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DOI：
10.1136/jmedgenet-2015-103263
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发表时间：
2016-05
影响因子：
4
通讯作者：
Scott RH
中科院分区：
文献类型：
--
作者：
Trump N;McTague A;Brittain H;Papandreou A;Meyer E;Ngoh A;Palmer R;Morrogh D;Boustred C;Hurst JA;Jenkins L;Kurian MA;Scott RH
我们试图调查早期发作的癫痫和严重发育迟缓的疾病的诊断率和基因突变谱。在400名患有这些疾病的患者中，没有已知的潜在病因，也没有主要的脑结构异常，我们使用Illumina MiSeq平台上的靶向测序和靶向外显子水平微阵列拷贝数分析的组合分析了46个基因。我们在71/400例患者（18%）中发现了致病突变。在出生后的前两个月内癫痫发作的患者中诊断率最高（39%），尽管总体上在有癫痫发作和无癫痫发作的患者中诊断率相似。最常见的突变基因是SCN 2A（11例患者，3%）。其他复发突变的基因包括CDKL 5、KCNQ 2、SCN 8A（各6例患者）、FOXG 1、MECP 2、SCN 1A、STXBP 1（各5例患者）、KCNT 1、PCDH 19、TCF 4（各3例患者）和ATP 1A 3、PRRT 2和SLC 9A 6（各2例患者）。EHMT 1、GABRB 3、LGI 1、MBD 5、PIGA、UBE 3A和ZEB 2的突变均在单个患者中发现。我们发现，在一些基因突变的患者，无论是电临床功能或畸形表型是非典型的基因。只有11例（15%）在检测前有足够的确定性将突变基因指定为可能的原因。我们的数据证明了基因面板方法在诊断早发性癫痫和严重发育迟缓障碍患者中的相当大的实用性。他们提供了进一步的见解表型谱和基因型-表型相关性的一些致病基因，并强调外显子水平的拷贝数测试在他们的分析价值。
We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. We identified causative mutations in 71/400 patients (18%). The diagnostic rate was highest among those with seizure onset within the first two months of life (39%), although overall it was similar in those with and without seizures. The most frequently mutated gene was SCN2A (11 patients, 3%). Other recurrently mutated genes included CDKL5, KCNQ2, SCN8A (six patients each), FOXG1, MECP2, SCN1A, STXBP1 (five patients each), KCNT1, PCDH19, TCF4 (three patients each) and ATP1A3, PRRT2 and SLC9A6 (two patients each). Mutations in EHMT1, GABRB3, LGI1, MBD5, PIGA, UBE3A and ZEB2 were each found in single patients. We found mutations in a number of genes in patients where either the electroclinical features or dysmorphic phenotypes were atypical for the identified gene. In only 11 cases (15%) had the clinician sufficient certainty to specify the mutated gene as the likely cause before testing. Our data demonstrate the considerable utility of a gene panel approach in the diagnosis of patients with early-onset epilepsy and severe developmental delay disorders., They provide further insights into the phenotypic spectrum and genotype–phenotype correlations for a number of the causative genes and emphasise the value of exon-level copy number testing in their analysis.