Genetic architecture of developmental disorders The genetics of developmental disorders (DDs) is complex. Martin et al. wanted to determine the degree of recessive inheritance of DDs in protein-coding genes. They examined the exomes of more than 6000 families in populations with high and low proportions of consanguineous marriages. They found that 3.6% of DDs in individuals of European ancestry involved recessive coding disorders, less than a tenth of the levels previously estimated. Furthermore, among South Asians with high parental relatedness, rather than most of the disorders arising from inherited variants, fewer than half had a recessive coding diagnosis. Science, this issue p. 1161 Exome sequencing of more than 6000 families identifies a lower rate of recessive inheritance than previously estimated. We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

中文翻译：

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量化隐性编码变异对发育障碍的贡献

发育障碍的遗传结构 发育障碍 (DD) 的遗传学很复杂。马丁等人。想确定蛋白质编码基因中DDs的隐性遗传程度。他们检查了 6000 多个家庭的外显子组，这些家庭的近亲婚姻比例高和低。他们发现，在欧洲血统的个体中，3.6% 的 DD 涉及隐性编码障碍，不到之前估计的水平的十分之一。此外，在与父母亲缘关系高的南亚人中，与大多数由遗传变异引起的疾病相比，只有不到一半的人具有隐性编码诊断。科学，本期第 3 页。1161 对 6000 多个家庭的外显子组测序确定了比先前估计的更低的隐性遗传率。我们估计了来自解密发育障碍研究的 6040 个家庭中隐性编码变异的全基因组贡献。在欧洲血统的患者中，可归因于隐性编码变异的病例比例为 3.6%，而由从头编码突变解释的病例比例为 50%。由于自合子性升高，巴基斯坦血统患者的这一比例更高（31%）。这种隐性负担的一半归因于已知基因。我们确定了两个以前与隐性发育障碍无关的基因，KDM5B 和 EIF3F，并用小鼠和细胞模型对它们进行了功能验证。我们的研究结果表明，隐性编码变体占目前未确诊的非近亲个体的一小部分，并且非编码变体的作用、不完全外显率、