Heterozygous missense variants in the WD repeat domain 11 (WDR11) gene are associated with hypogonadotropic hypogonadism in humans. In contrast, knockout of both alleles of Wdr11 in mice results in a more severe phenotype with growth and developmental delay, features of holoprosencephaly, heart defects and reproductive disorders. Similar developmental defects known to be associated with aberrant hedgehog signaling and ciliogenesis have been found in zebrafish after Wdr11 knockdown. We here report biallelic loss-of-function variants in the WDR11 gene in six patients from three independent families with intellectual disability, microcephaly and short stature. The findings suggest that biallelic WDR11 variants in humans result in an overlapping but milder phenotype compared to Wdr11-deficient animals. However, the observed human phenotype differs significantly from dominantly inherited variants leading to hypogonadotropic hypogonadism, suggesting that recessive WDR11 variants result in a clinically distinct entity.

WD 重复结构域 11 ( WDR11 ) 基因中的杂合错义变体与人类的促性腺功能减退症有关。相比之下，在小鼠中敲除Wdr11的两个等位基因会导致更严重的表型，包括生长和发育迟缓、前脑全裂、心脏缺陷和生殖障碍的特征。在Wdr11敲低后，在斑马鱼中发现了与异常刺猬信号和纤毛发生相关的类似发育缺陷。我们在这里报告了来自三个独立家庭的六名患有智力残疾、小头畸形和身材矮小的患者的WDR11基因的双等位基因功能丧失变异体。研究结果表明双等位基因与Wdr11 缺陷动物相比，人类中的WDR11变体导致重叠但更温和的表型。然而，观察到的人类表型与导致促性腺功能减退症的显性遗传变异显着不同，这表明隐性WDR11变异导致临床上不同的实体。