Pathogenicity and selective constraint on variation near splice sites
Pathogenicity and selective constraint on variation near splice sites
复制标题
DOI：
10.1101/gr.238444.118
复制
发表时间：
2019-02-01
期刊：
影响因子：
7
通讯作者：
Hurles, Matthew E.
中科院分区：
文献类型：
--
作者：
Lord, Jenny;Gallone, Giuseppe;Hurles, Matthew E.
干扰正常前mrna剪接的突变是导致人类疾病的重要因素。我们利用7833个发育障碍（dd）先显子及其未受影响父母的外显子组测序数据，以及来自外显子组聚集联盟（exome Aggregation Consortium）的6万多个聚合外显子组，研究剪接位点周围的选择，并量化剪接突变对dd的贡献。净化选择的模式，健康受试者中高度受限基因的变异缺陷，以及患者中过多的新生突变，突出了共识剪接位点内部和周围的特定位置，具有更大的功能相关性。通过突变负担分析，我们可以以无偏的方式估计典型二核苷酸（73%）和侧翼非典型位点（27%）突变的相对贡献，并计算不同类型突变的致病性的阳性预测值。我们确定了18例在剪接位点非规范位置的显性dd相关基因可能有诊断性新生突变的患者。我们估计35%-40%的非规范剪接位点的致病变异在公共数据库中缺失。
Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases.