Comorbidity of holoprosencephaly (HPE) and congenital heart disease (CHD) in individuals with genetic variants in known HPE-related genes has been recurrently observed. Morphogenesis of the brain and heart from very early stages are regulated by several biological pathways, some of them involved in both heart and brain development as evidenced by genetic studies on model organisms. For instance, downregulation of Hedgehog or Nodal signaling pathways, both known as major triggers of HPE, has been shown to play a role in the pathogenesis of CHD, including structural defects and left-right asymmetry defects. In this study, individuals with various types of HPE were investigated clinically and by genomic sequencing. Cardiac phenotypes were assessed in 434 individuals with HPE who underwent targeted sequencing. CHDs were identified in 8% (n = 33) of individuals, including 10 (30%) cases of complex heart disease. Only four individuals (4/33) had damaging variants in the known HPE genes STAG2, SIX3, and SHH. Interestingly, no CHD was identified in the 37 individuals of our cohort with pathogenic variants in ZIC2. These findings suggest that CHD occurs more frequently in HPE-affected individuals with or without identifiable genetic variants, and this co-occurrence may be genetically driven and gene-specific.

中文翻译：

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先天性心脏缺陷和前脑无裂畸形的合并症可能是遗传驱动的且具有基因特异性。


在已知 HPE 相关基因具有遗传变异的个体中，经常观察到前脑无裂畸形 (HPE) 和先天性心脏病 (CHD) 的共病。大脑和心脏的形态发生从很早开始就受到多种生物途径的调节，其中一些生物途径涉及心脏和大脑的发育，对模式生物的遗传研究证明了这一点。例如，Hedgehog 或 Nodal 信号通路的下调（两者均被称为 HPE 的主要触发因素）已被证明在 CHD 的发病机制中发挥作用，包括结构缺陷和左右不对称缺陷。在这项研究中，对患有各种类型 HPE 的个体进行了临床和基因组测序研究。对 434 名接受靶向测序的 HPE 患者进行了心脏表型评估。 8% (n = 33) 的个体患有 CHD，其中 10 例 (30%) 患有复杂心脏病。只有 4 个人 (4/33) 在已知的 HPE 基因 STAG2、SIX3 和 SHH 中存在破坏性变异。有趣的是，我们队列中 37 名携带 ZIC2 致病性变异的个体中没有发现 CHD。这些发现表明，CHD 在具有或不具有可识别遗传变异的 HPE 影响的个体中更频繁地发生，并且这种同时发生可能是遗传驱动的和基因特异性的。