Fetal brain arrest is an extremely rare genetic disorder that was described in few patients and encompasses very unique findings of underdeveloped cerebral hemispheres in association with collapsed skull bones. Based on the recurrence among sibs, an autosomal recessive mode of inheritance was proposed; however, no causative gene was identified so far. Here, we report the identification of biallelic variants in the WDR81 gene in two unrelated families (4 patients) with fetal brain arrest including the originally described family and an additional new family. Two homozygous variants were identified: a new missense (c.1157 T > C, p.Val386Ala) and a previously described frameshift variant, c.4668_4669delAG (p.Gly1557AspfsTer16). We assessed the expression of WDR81 at the protein level by western blot analysis using primary skin fibroblast cultures established from the patient with the missense variant and noticed that WDR81 expression was significantly reduced in comparison to normal control confirming the pathogenicity of this variant. Our findings confirm the involvement of WDR81 in the pathogenesis of fetal brain arrest syndrome and suggest that fetal brain arrest represents the severe end of the spectrum phenotypes caused by pathogenic variants in WDR81. In addition, we reviewed the clinical and molecular data on WDR81-related disorders and phenotype/genotype correlations.

胎儿脑停搏是一种极为罕见的遗传疾病，在少数患者中被描述过，并且包括非常独特的大脑半球发育不全与颅骨塌陷相关的发现。基于同胞间的复发，提出了常染色体隐性遗传方式；然而，到目前为止，还没有发现致病基因。在这里，我们报告了WDR81基因中双等位基因变异的鉴定，这些变异在两个不相关的胎儿脑骤停家族（4 名患者）中发现，包括最初描述的家族和一个额外的新家族。鉴定了两个纯合变体：一个新的错义（c.1157 T > C，p.Val386Ala）和一个先前描述的移码变体，c.4668_4669delAG（p.Gly1557AspfsTer16）。我们评估了WDR81的表达使用从具有错义变体的患者建立的原代皮肤成纤维细胞培养物通过蛋白质印迹分析在蛋白质水平上，并注意到与正常对照相比，WDR81表达显着降低，证实了该变体的致病性。我们的研究结果证实了WDR81参与了胎儿脑停搏综合征的发病机制，并表明胎儿脑停搏代表了由WDR81致病变异引起的谱表型的严重终结。此外，我们回顾了WDR81相关疾病和表型/基因型相关性的临床和分子数据。