Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population.
Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population.
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DOI：
10.1016/j.ajhg.2022.05.011
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发表时间：
2022-07-07
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
已知许多罕见的单基因疾病是由数千个基因中的有害变异引起的，然而，在没有相关临床表型的人中也可以发现相同的变异。这些单基因变异的外显性在更广泛的人群中通常是未知的，因为它们通常在具有高渗透性变异的受影响个人和家庭的小临床队列中被发现。在这里，我们研究了基因和基因座中罕见的、潜在有害的变异的表型效应，其中类似的变异已知会在大量人群中导致单基因发育障碍(DDS)。我们使用UK Biobank研究了与599个单等位基因DDG2P基因的罕见蛋白质截断和错义变异相关的表型，方法是使用来自∼200,000个个体的全外显子组测序数据，以及使用来自∼500,000个个体的SNP阵列数据来研究与已知DD基因座重叠的罕见拷贝数变异的表型。我们发现，与英国Biobank队列的其他成员相比，具有这些可能有害变异的个体具有轻微的DD相关表型，包括较低的液体智力、较慢的反应时间、较低的数字记忆分数和较长的配对时间。他们也更矮，有更高的BMI，并且有显著的社会经济劣势：他们不太可能被就业或工作，收入更低，贫困指数更高。我们的发现表明，许多在儿科遗传学中常规测试的基因具有中等外显性的有害变异，可能会导致普通成年人终生亚临床表型。
Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DDs) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes by using whole-exome-sequencing data from ∼200,000 individuals and rare copy-number variants overlapping known DD loci by using SNP-array data from ∼500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores, and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, had a higher BMI, and had significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and higher deprivation index. Our findings suggest that many genes routinely tested within pediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong sub-clinical phenotypes in the general adult population.
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影响因子：
3.9
作者：
Qi, Hongjian;Dong, Chengliang;Chung, Wendy K.;Wang, Kai;Shen, Yufeng
通讯作者：
Shen, Yufeng
影响因子：
5
作者：
Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
11
作者：
Plomin, R.;Deary, I. J.
通讯作者：
Deary, I. J.
影响因子：
30.8
作者：
Cooper, Gregory M.;Coe, Bradley P.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.