Variant of the catalytic cysteine of UFSP2 leads to spondyloepimetaphyseal dysplasia type Di Rocco.

Spondyloepimetaphyseal dysplasia (SEMD) is characterized by vertebral, epiphyseal, and metaphyseal alterations. Patients become predominantly apparent with disproportionate short stature. The genetic background of SEMD is heterogeneous, with different modes of inheritance (autosomal dominant, autosomal recessive, and X-linked disorders). Amongst the genes in which variants are known to cause SEMD, UFM1-specific protease 2 (UFSP2) encodes a cysteine protease involved in the maturation of Ubiquitin-fold modifier 1 (UFM1). Heterozygous pathogenic variants affecting the C-terminal catalytic domain of UFSP2 are related to two entities of skeletal dysplasia, Beukes hip dysplasia (BHD) and SEMD type Di Rocco (SEMDDR). This is the first report of a de novo heterozygous variant affecting the catalytic Cys302 residue of UFSP2 (NM_018359.3:c.905G>C, p.(Cys302Ser)) causing SEMDDR. According to previously described patients with SEMDDR, our patient presented with disproportionate short stature, genu varum, gait instability, and radiologically detected epiphyseal and metaphyseal alterations. Additionally, a bell-shaped thorax, lumbar hyperlordosis, muscular hypotonia, and coxa vara were observed in the patient described in this study. Our findings underline the fundamental importance of an intact catalytic triad of the human UFSP2 for normal skeletal development and extend the phenotypical features of patients with UFSP2-related skeletal dysplasia.

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

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.