Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability

Abstract

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.

Fig. 1. 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 in [1] and the identified coding variants in family A (red) and family B (blue).

Fig. 2. Expression analysis of the homozygous WDR11Q419* variant.

a WDR11Q419* leads to loss of WDR11 protein in patient fibroblasts. Immunostaining of control (upper panel) and WDR11^Q419* fibroblasts (lower panel) with antibodies against WDR11 (green; Abcam, ab93871) and the Golgi/TGN marker Golgin97 (red; Molecular Probes, A-21270). Control cells show strong juxtanuclear WDR11 staining, while WDR11^Q419* fibroblasts only show weak and unspecific background labeling. Scale bar, 10 µm. b Quantification of WDR11 signal intensities. Small images to the right show exemplary cells of two different control (Ctrl 1, Ctrl 2) and WDR11^Q419* fibroblasts stained with anti-WDR11 antibodies (ab93871, green) used for quantification. Nuclear counterstain: DAPI. Data represent mean ± SEM, n number of analyzed cells. ***P < 0.0001; One-way ANOVA, Bonferroni’s multiple comparisons test. Scale bar, 20 µm. RFU: relative fluorescence units. c Western blot analyses show WDR11 expression in 4 independent control fibroblasts (130 kDa) but complete absence in patient III-1 of family A (2 independent experiments). No truncated WDR11 protein fragments were evident in patient’s lysate (see also Supplementary Fig. 1). N-term N-Terminus, antibody recognizing epitope aa268–348, C-term C-terminus, antibody recognizing epitope aa1174–1224.