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 (2−5) 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.

已知大量基因中的罕见破坏性变异会导致单基因发育障碍（DD），并且还被证明会在人群中导致较温和的亚临床表型。在这里，我们表明，在 599 个显性 DD 基因中携带多个 (2−5) 罕见破坏性变异对英国生物银行中的许多认知和社会经济特征具有附加的不利影响，这可以通过较高的教育程度多基因评分来部分抵消 (EA- PGS）。与预期 EA-PGS 的表型偏差可以部分解释为罕见 DD 变体的富集或耗尽。在罕见 DD 变异的携带者中，有 DD 相关临床诊断的携带者的 EA-PGS 明显低于没有临床诊断的携带者，并且表型更严重。我们的结果表明，罕见和常见变异的总体负担可以改变表型的表达性，从而可能影响个体是否达到临床疾病的阈值。