Clustering of predicted loss-of-function variants in genes linked with monogenic disease can explain incomplete penetrance
Clustering of predicted loss-of-function variants in genes linked with monogenic disease can explain incomplete penetrance
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与单基因疾病相关的基因中预测的功能丧失变异的聚类可以解释不完全外显率
DOI：
10.1101/2023.10.11.23296535
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Beaumont R
中科院分区：
文献类型：
--
作者：
Beaumont R
背景严重改变蛋白质产物的遗传变异（例如无义、移码）通常与疾病相关。对于一些基因，这些预测的功能丧失变体（pLoF）在整个基因中观察到，而在其他基因中，它们仅发生在特定位置。我们假设，对于与显示不完全突变的单基因疾病相关的基因，存在于明显未受影响的个体中的pLoF变体可能仅限于pLoF耐受的区域。为了测试这一点，我们调查是否pLoF的位置可以解释预计是致病性的孟德尔conditions.MethodsWe使用外显子组序列数据在454，773个人在英国生物银行（UKB）调查的pLoF的位置在人口队列的变异不完全突变的情况。我们计算了所有蛋白质编码基因的编码序列（CDS）的每个五分位数中UKB中独特的pLoF、错义和同义变体的数量，并使用高斯混合模型对变体进行聚类。我们将分析限制在每种类型具有≥ 5个变体的基因（16，473个基因）。我们比较了pLoF在UKB中的位置与转录本中所有理论上可能的pLoF，以及来自ClinVar的致病性pLoF，并进行了模拟以估计非均匀分布的变体的假阳性率。但是，单倍不足导致发育障碍的基因与其他基因相比，不太可能具有均匀的pLoF分布（P< 2.2 × 10−6）。我们鉴定了许多基因，包括ARID1BandGATA6，其中CDS第一个四分之一的pLoF变体被替代翻译起始位点的存在所拯救，不应报告为致病性。对于其他基因，如asODC 1，pLoFs位于整个基因大致均匀，但致病性pLoFs仅在末端聚集，符合功能获得性疾病mechanism.ConclusionsOur结果表明本地化的约束指标的潜在好处，pLoF变体的位置时，应考虑解释的变体。
BackgroundGenetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease. For some genes, these predicted loss-of-function variants (pLoFs) are observed throughout the gene, whilst in others, they occur only at specific locations. We hypothesised that, for genes linked with monogenic diseases that display incomplete penetrance, pLoF variants present in apparently unaffected individuals may be limited to regions where pLoFs are tolerated. To test this, we investigated whether pLoF location could explain instances of incomplete penetrance of variants expected to be pathogenic for Mendelian conditions.MethodsWe used exome sequence data in 454,773 individuals in the UK Biobank (UKB) to investigate the locations of pLoFs in a population cohort. We counted numbers of unique pLoF, missense, and synonymous variants in UKB in each quintile of the coding sequence (CDS) of all protein-coding genes and clustered the variants using Gaussian mixture models. We limited the analyses to genes with ≥ 5 variants of each type (16,473 genes). We compared the locations of pLoFs in UKB with all theoretically possible pLoFs in a transcript, and pathogenic pLoFs from ClinVar, and performed simulations to estimate the false-positive rate of non-uniformly distributed variants.ResultsFor most genes, all variant classes fell into clusters representing broadly uniform variant distributions, but genes in which haploinsufficiency causes developmental disorders were less likely to have uniform pLoF distribution than other genes (P< 2.2 × 10−6). We identified a number of genes, includingARID1BandGATA6, where pLoF variants in the first quarter of the CDS were rescued by the presence of an alternative translation start site and should not be reported as pathogenic. For other genes, such asODC1, pLoFs were located approximately uniformly across the gene, but pathogenic pLoFs were clustered only at the end, consistent with a gain-of-function disease mechanism.ConclusionsOur results suggest the potential benefits of localised constraint metrics and that the location of pLoF variants should be considered when interpreting variants.
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影响因子：
9.8
作者：
Coban-Akdemir, Zeynep;White, Janson J.;Carvalho, Claudia M. B.
通讯作者：
Carvalho, Claudia M. B.
影响因子：
16.6
作者：
Kurki, Mitja I.;Saarentaus, Elmo;Palotie, Aarno
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估计基于面板的基因组分析中的诊断噪声
DOI：
10.1101/2022.03.18.22272595
发表时间：
2022
期刊：
--
影响因子：
--
作者：
Beaumont R
通讯作者：
Beaumont R
影响因子：
9.8
作者：
通讯作者：
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影响因子：
4.1
作者：
Schultz, Chad R.;Bupp, Caleb P.;Bachmann, Andre S.
通讯作者：
Bachmann, Andre S.