PDF(Pubmed)
Abstract：
Protein-truncating variants (PTVs) near the 3\' end of genes may escape nonsense-mediated decay (NMD). PTVs in the NMD-escape region (PTVescs) can cause Mendelian disease but are difficult to interpret given their varying impact on protein function. Previously, PTVesc burden was assessed in an epilepsy cohort, but no large-scale analysis has systematically evaluated these variants in rare disease. We performed a retrospective analysis of 29,031 neurodevelopmental disorder (NDD) parent-offspring trios referred for clinical exome sequencing to identify PTVesc de novo mutations (DNMs). We identified 1,376 PTVesc DNMs and 133 genes that were significantly enriched (binomial p < 0.001). The PTVesc-enriched genes included those with PTVescs previously described to cause dominant Mendelian disease (e.g., SEMA6B, PPM1D, and DAGLA). We annotated ClinVar variants for PTVescs and identified 948 genes with at least one high-confidence pathogenic variant. Twenty-two known Mendelian PTVesc-enriched genes had no prior evidence of PTVesc-associated disease. We found 22 additional PTVesc-enriched genes that are not well established to be associated with Mendelian disease, several of which showed phenotypic similarity between individuals harboring PTVesc variants in the same gene. Four individuals with PTVesc mutations in RAB1A had similar phenotypes including NDD and spasticity. PTVesc mutations in IRF2BP1 were found in two individuals who each had severe immunodeficiency manifesting in NDD. Three individuals with PTVesc mutations in LDB1 all had NDD and multiple congenital anomalies. Using a large-scale, systematic analysis of DNMs, we extend the mutation spectrum for known Mendelian disease-associated genes and identify potentially novel disease-associated genes.
摘要：
基因3'末端附近的蛋白质截断变体（PTV）可能会逃脱无义介导的衰变（NMD）。NMD逃逸区（PTVess）中的PTV可引起孟德尔病，但由于它们对蛋白质功能的不同影响，因此难以解释。以前,在癫痫队列中评估PTVesc负担，但是没有大规模的分析在罕见疾病中系统地评估这些变异。我们对29,031个神经发育障碍（NDD）亲本-后代三重奏进行了回顾性分析，用于临床外显子组测序，以鉴定PTVesc新生突变（DNM）。我们鉴定了1,376个PTVescDNM和133个显著富集的基因(二项p<0.001)。富含PTVesc的基因包括先前描述的导致显性孟德尔疾病的PTVesc基因（例如，SEMA6B,PPM1D,和DAGLA）。我们注释了PTVescs的ClinVar变体，并鉴定了948个具有至少一个高置信度致病性变体的基因。22个已知的富含孟德尔PTVesc的基因没有PTVesc相关疾病的先前证据。我们发现了另外22个富含PTVesc的基因，这些基因与孟德尔疾病相关，其中一些显示在同一基因中携带PTVesc变体的个体之间的表型相似性。RAB1A中具有PTVesc突变的四个个体具有相似的表型，包括NDD和痉挛。在两个个体中发现了IRF2BP1中的PTVesc突变，每个个体在NDD中表现出严重的免疫缺陷。LDB1中PTVesc突变的三名个体均患有NDD和多种先天性异常。使用大规模，对DNM的系统分析，我们扩展了已知孟德尔疾病相关基因的突变谱,并鉴定了潜在的新疾病相关基因.
