Heterozygous loss of OSR2 can cause radioulnar synostosis with ancillary skeletal manifestations.

Abstract

Although radioulnar synostosis (RUS) and other skeletal anomalies are features of the 8q22.2q22.3 microdeletion syndrome, the precise genetic etiology of RUS remains undefined. Here, we aimed to define the genetic basis of joint fusion in this syndrome. We performed combined chromosomal microarray, high-throughput ligation-dependent probe amplification, and exome sequencing on RUS probands and families. Variant effects were assessed through structural modeling, Western blot, and immunofluorescence. Murine Osr2 knockout phenotypes were evaluated via literature review. A 383.28-kb heterozygous deletion at 8q22.2 (arr[GRCh37] 8q22.2(99903192_100286471)x1), completely encompassing OSR2 (HGNC:15830), was identified in a mother-son pair with RUS. Exome sequencing revealed OSR2 variants in 5 unrelated pedigrees: the nonsense variant c.481C>T p.(Arg161Ter) in 2 families, c.174T>A p.(Tyr58Ter) in 1 family, and 2 missense variants (c.628C>T p.(Arg210Trp) and c.628C>G p.(Arg210Gly), each in 1 family. Clinical reevaluation identified additional phenotypes, including distal ulna hypoplasia, joint stiffness, ear deformity, scoliosis, and short stature in individuals harboring OSR2 variants. Functional studies demonstrated loss-of-function mechanisms (absent/truncated protein or impaired nuclear localization). Literature showed Osr2 knockout mice phenocopied human joint fusion. This study links OSR2 haploinsufficiency or loss-of-function variants to RUS and other skeletal malformations.