NKX2‐5 is a homeodomain transcription factor that plays a crucial role in heart development. It is the first gene where a single genetic variant (GV) was found to be associated with congenital heart diseases in humans. In this study, we carried out a comprehensive survey of NKX2‐5 GVs to build a unified, curated, and updated compilation of all available GVs. We retrieved a total of 1,380 unique GVs. From these, 970 had information on their frequency in the general population and 143 have been linked to pathogenic phenotypes in humans. In vitro effect was ascertained for 38 GVs. The homeodomain had the biggest cluster of pathogenic variants in the protein: 49 GVs in 60 residues, 23 in its third α‐helix, where 11 missense variants may affect protein–DNA interaction or the hydrophobic core. We also pinpointed the likely location of pathogenic GVs in four linear motifs. These analyses allowed us to assign a putative explanation for the effect of 90 GVs. This study pointed to reliable pathogenicity for GVs in helix 3 of the homeodomain and may broaden the scope of functional and structural studies that can be done to better understand the effect of GVs in NKX2‐5 function.

中文翻译：

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NKX2-5 遗传变异的更新。

NKX2-5是一种同源域转录因子，在心脏发育中起着至关重要的作用。它是第一个发现单一遗传变异 (GV) 与人类先天性心脏病相关的基因。在本研究中，我们对NKX2-5GV 以构建所有可用 GV 的统一、精选和更新的汇编。我们总共检索了 1,380 个独特的 GV。其中，970 人掌握了它们在一般人群中的频率信息，143 人与人类的致病表型有关。确定了 38 个 GV 的体外效果。同源域具有蛋白质中最大的致病变异簇：60 个残基中有 49 个 GV，其第三个 α-螺旋中有 23 个，其中 11 个错义变异可能影响蛋白质-DNA 相互作用或疏水核心。我们还确定了四个线性基序中致病 GV 的可能位置。这些分析使我们能够为 90 GV 的影响指定一个假定的解释。NKX2-5功能。