Fetal brain arrest broadens the spectrum of WDR81-related developmental brain malformations

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.

Automated summary

This study identified biallelic variants in the WDR81 gene in two unrelated families with fetal brain arrest, confirming the involvement of the gene in the syndrome and suggesting phenotypic correlations with pathogenic variants in WDR81. The reduced expression of WDR81 in patient fibroblast cultures with the missense variant supports the pathogenicity of the identified variants.