Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population
Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population
复制标题
显性发育障碍基因座中的罕见遗传变异导致一般人群中较温和的相关表型
DOI：
10.1101/2021.12.15.21267855
复制
发表时间：
2021
影响因子：
3.2
通讯作者：
C. Wright
中科院分区：
文献类型：
--
作者：
R. Kingdom;M. Tuke;A. Wood;R. Beaumont;T. Frayling;M. Weedon;C. Wright
众所周知，许多罕见疾病是由孟德尔基因的有害变异引起的，然而，在没有相关临床表型的人群中也可以发现相同的变异。这些单基因变异的外显率在更广泛的人群中通常是未知的，因为它们通常是在具有高外显率变异的受影响个体和家庭的小型临床队列中发现的。在这里，我们研究了已知导致单基因发育障碍（DD）的基因和位点中罕见的潜在有害变异的表型效应。我们使用UK Biobank，利用来自约20万个体的全外显子组测序数据，研究了599个显性DD基因中罕见的蛋白质截断和错义变异的相关表型，并利用来自约50万个体的snp阵列数据，研究了与已知DD位点重叠的罕见拷贝数变异。我们发现，与英国生物银行的其他队列相比，具有这些可能有害变异的个体具有轻度的dd相关表型，包括较低的流体智力，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，身体质量指数更高，有明显的社会经济劣势，就业或工作的可能性更小，收入更低，剥夺指数更高。我们的研究结果表明，在儿科遗传学中常规检测的许多单基因DD基因具有中等外显率，并且可能在一般成人人群中导致终生轻度亚临床表型。
Many rare diseases are known to be caused by deleterious variants in Mendelian 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 that are known to cause monogenic developmental disorders (DD) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 dominant DD genes using whole exome sequencing data from ~200,000 individuals, and rare copy number variants overlapping known DD loci 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, with a higher BMI and had significant socioeconomic disadvantages, being less likely to be employed or be able to work, and having a lower income and higher deprivation index. Our findings suggest that many monogenic DD genes routinely tested within paediatric genetics have intermediate penetrance and may cause lifelong milder, sub-clinical phenotypes in the general adult population.