The genetic basis of congenital heart malformations associated with disruption of left-right (L-R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left-right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab-Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left-right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.

中文翻译：

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GDF1中的创建者截断变体在多种阿拉伯亲戚中导致常染色体隐性右异构现象和相关的先天性心脏缺陷。

与左右（LR）不对称性破坏相关的先天性心脏畸形的遗传基础是广泛而异质的，迄今为止涉及超过25个基因的变异。其中，迄今报道的23名单等位基因或双等位基因个体中，生长/分化因子1（GDF1）基因中的有害变异体已显示出异型异位，伴有左右模式的复杂心脏畸形。我们报告了三个不相关的个​​体表现出先天性心脏缺陷的右异构现象，每个都起源于近亲的阿拉伯-穆斯林血统。使用整个外显子组测序，揭示了在GDF1基因中共有的新的纯合的截短的c.608G> A（p.W203 *）变异体是其疾病的分子基础。后来，该变体的定向测序表明，在这些家庭中，该病与疾病完全隔离，据报道共有15个以上的受影响个体，从而可以进行遗传咨询，产前诊断和计划未来的怀孕。我们的发现进一步证实了双等位基因GDF1变体，异型性和先天性心脏病左右模式的关联，并扩展了先前描述的表型谱和突变谱。此外，我们建议在相关临床情况下针对p.W203 *变体进行靶向筛查。异质性和先天性心脏缺陷的左右模式，并扩展了先前描述的表型谱和突变谱。此外，我们建议在相关临床情况下针对p.W203 *变体进行靶向筛查。异质性和先天性心脏缺陷的左右模式，并扩展了先前描述的表型谱和突变谱。此外，我们建议在相关临床情况下针对p.W203 *变体进行靶向筛查。