Biallelic Variants inCCN2Underlie an Autosomal Recessive Kyphomelic Dysplasia

Abstract

AbstractKyphomelic dysplasia is a rare heterogenous group of skeletal dysplasia, characterized by bowing of the limbs, severely affecting femora with distinct facial features. Despite its first description nearly four decades, the precise molecular basis of this condition remained elusive until the recent discovery ofde novovariants in the KIF5B-related kyphomelic dysplasia. We ascertained two unrelated consanguineous families with kyphomelic dysplasia. They had six affected offsprings and we performed a detailed clinical evaluation, skeletal survey, and exome sequencing in three probands. All the probands had short stature, cleft palate, and micro-retrognathia. Radiographs revealed kyphomelic femora, bowing of long bones, radial head dislocations and spondyloepimetaphyseal dysplasia. We noted two novel homozygous variants inCCN2as possible candidates that segregated with the phenotype in the families: a missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5.CCN2is crucial for proliferation and differentiation of chondrocytes. Earlier studies have shown thatCcn2-deficient mice exhibit twisted limbs, short and kinked sterna, broad vertebrae, domed cranial vault, shorter mandibles, cleft palate and impaired osteoclastogenesis. We studied the impact ofCCN2knockout in zebrafish models via CRISPR-Cas9 gene editing. F0 knockouts ofccn2ain zebrafish showed altered body curvature, impaired cartilage formation in craniofacial region and either bent or missing tails recapitulating the human phenotype. Our observations in humans and zebrafish combined with previously described skeletal phenotype ofCcn2knock out mice, confirm that biallelic loss of function variants inCCN2result in an autosomal recessive kyphomelic dysplasia.