Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.
Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.
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DOI：
10.1371/journal.pgen.1006335
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发表时间：
2016-10
期刊：
影响因子：
4.5
通讯作者：
Andelfinger G
中科院分区：
文献类型：
--
作者：
Preuss C;Capredon M;Wünnemann F;Chetaille P;Prince A;Godard B;Leclerc S;Sobreira N;Ling H;Awadalla P;Thibeault M;Khairy P;MIBAVA Leducq consortium;Samuels ME;Andelfinger G
左心室流出道梗阻（LVOTO）包括广泛的表型异质性心脏畸形，经常聚集在家庭。我们对来自51个有多个受影响成员的家庭的182名个体进行了基于家庭的全外显子组和靶向重测序。我们的方法的核心是家庭单位，作为一个参考，以确定因果基因型-表型相关性。筛选了10个重叠表型，在12个家族中发现了疾病相关和共分离的变异体。这些罕见的或新的改变蛋白质的突变主要聚集在沿着Notch信号级联的基因（NOTCH 1、ARHGAP 31、MAML 1、SMARCA 4、JARID 2、JAG 1）中。这与患者中与对照相比在Notch信号传导途径中具有更高致病性的变体的显著富集（Wilcoxon，p< 0.05）一致。NOTCH 1中新型蛋白质截短和错义突变的显著富集突出了我们儿科队列中的等位基因和表型异质性。我们在三个独立的家族共15个受影响的个体中发现了与左右侧心脏畸形相关的NOTCH 1新的共分离致病性突变。总之，我们的研究结果表明，家族特异性突变沿着Notch级联的小部分但高致病性是LVOTO的常见原因。左心室流出道梗阻包括一组发育性心脏疾病，这些疾病在遗传和表型上都是异质性的，大多数病例没有单一基因。为了确定导致疾病的突变，我们从51个有先天性心脏畸形病史的家族中选择了患者。我们询问了106名患者的整个编码序列，并确定了一个小的，但高致病性的突变，可能有助于疾病的12个家庭（23.5%）。此外，我们提出了一种基于遗传异质性疾病的家族分离来识别候选突变的策略。
Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO. Left-ventricular outflow tract obstructions comprise a group of developmental heart disorders that are genetically and phenotypically heterogeneous, with no single gene accounting for the majority of cases. In order to identify mutations contributing to disease, we selected patients from 51 families with a history of congenital cardiac malformations. We interrogated the entire coding sequences of 106 patients and identified a small but highly pathogenic fraction of mutations that are likely to contribute to disease in 12 families (23.5%). Furthermore, we present a strategy for identifying candidate mutations based on familial segregation in a genetically heterogeneous disorder.
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