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

Natja Haag,Stephanie Ditroia,Christopher A Walsh,Jennifer E Neil,Matthias Begemann,Ganeshwaran H Mochida,Cordula Knopp,Ene-Choo Tan,Florian Kraft,Muna Al-Saffar,Lars Buschmann,Laila Bastaki,Ingo Kurth,Lynn Pais,Angeline H M Lai,Petra Holschbach,Maggie Brett

doi:10.1038/s41431-021-00943-5

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.

Highlights

WDR11 encodes for the WD repeat domain 11 protein and has been shown to be broadly expressed in the developing central nervous system of mice [1]
We report biallelic loss-of-function variants in six affected individuals from three families who presented with intellectual disability, microcephaly and mild short stature
In this study, we report for the first time three unrelated families with the core features of intellectual disability, microcephaly, and mild short stature in whom genetic analysis revealed biallelic lossof-function variants in WDR11 (Table 1)

Summary

Introduction

WDR11 encodes for the WD repeat domain 11 protein and has been shown to be broadly expressed in the developing central nervous system of mice [1]. Heterozygous missense variants in the WDR11 gene have been associated with hypogonadotropic hypogonadism type 14 with or without anosmia (OMIM #614858) [1]. Congenital hypogonadotropic hypogonadism (CHH) is clinically characterized by pubertal failure and infertility due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH) and can be associated with various additional developmental defects [2]. Animal studies showed that Hedgehog (Hh) signaling in the primary cilium was impaired by loss of WDR11 [3]. Wdr11defective mice and zebrafish demonstrated complex developmental abnormalities indicative for aberrant Hh signaling and impaired ciliogenesis [3]. No human phenotype associated with biallelic variants in WDR11 has been described yet. We report biallelic loss-of-function variants in six affected individuals from three families who presented with intellectual disability, microcephaly and mild short stature

Methods

Results

Conclusion