Preuss Christoph, Capredon Melanie, Wünnemann Florian, Chetaille Philippe, Prince Andrea, Godard Beatrice, Leclerc Severine, Sobreira Nara, Ling Hua, Awadalla Philip, Thibeault Maryse, Khairy Paul, Samuels Mark E, Andelfinger Gregor
Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada.
Faculty of Biology, University of Muenster, Muenster, Germany.
PLoS Genet. 2016 Oct 19;12(10):e1006335. doi: 10.1371/journal.pgen.1006335. eCollection 2016 Oct.
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.
左心室流出道梗阻（LVOTO）涵盖了一系列表型异质性的心脏畸形，这些畸形在家族中常常聚集出现。我们对来自51个有多例患者的家族的182名个体进行了基于家族的全外显子组测序和靶向重测序。我们方法的核心是家族单位，它作为识别因果基因型-表型相关性的参照。筛查10种重叠的表型发现，12个家族中存在与疾病相关且共分离的变异。这些罕见或新的蛋白质改变突变主要聚集在Notch信号级联反应相关的基因（NOTCH1、ARHGAP31、MAML1、SMARCA4、JARID2、JAG1）中。这与患者中Notch信号通路中具有较高致病性的变异相比对照组有显著富集（Wilcoxon检验，p<0.05）相符。NOTCH1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。我们在三个独立家族中总共15名患者中鉴定出与左右侧心脏畸形相关的NOTCH1中新的共分离致病突变。总之，我们的结果表明，Notch级联反应中一小部分但具有高度致病性的家族特异性突变是LVOTO的常见病因。
