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 Wdr11knockdown. We here report biallelic loss-of-function variants in theWDR11 gene in six patients from three independent families with intellectual disability, microcephaly and short stature.
FIG: Pedigrees and schematic representation of all identified variants in this study: a Pedigrees of family A, B, and C. b Scheme of the WDR11 gene showing the identified variants in family A (red), family B (blue) and family C (green). c Linear map of the WDR11 protein (NP_060587.8) indicating the twelve WDR domains (blue) as described and the identified coding variants in family A (red) and family B (blue).
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.
Haag, N., Tan, EC., Begemann, M. et al. Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability. Eur J Hum Genet (2021). https://doi.org/10.1038/s41431-021-00943-5