英国埃克塞特大学Caroline F. Wright研究小组揭示，单基因发育障碍基因位点罕见变异的遗传修饰因子。2024年4月18日，《自然—遗传学》杂志在线发表了这项成果。

研究人员表示，众所周知，大量基因中的罕见损伤性变异会导致DD，而且在人群队列中也被证明会导致较轻的亚临床表型。

附：英文原文

Title: Genetic modifiers of rare variants in monogenic developmental disorder loci

Author: Kingdom, Rebecca, Beaumont, Robin N., Wood, Andrew R., Weedon, Michael N., Wright, Caroline F.

Issue&Volume: 2024-04-18

Abstract: Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown to cause milder subclinical phenotypes in population cohorts. Here, we show that carrying multiple (25) rare damaging variants across 599 dominant DD genes has an additive adverse effect on numerous cognitive and socioeconomic traits in UK Biobank, which can be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Phenotypic deviators from expected EA-PGS could be partly explained by the enrichment or depletion of rare DD variants. Among carriers of rare DD variants, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without a clinical diagnosis. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may then influence whether an individual reaches the threshold for clinical disease.

DOI: 10.1038/s41588-024-01710-0

Source: https://www.nature.com/articles/s41588-024-01710-0