ESPE Abstracts

Spondyloepimetaphyseal dysplasias (SEMDs), predominantly associated with disproportionate short stature, comprise a heterogeneous group of autosomal-dominant, autosomal-recessive, and X-linked recessive skeletal dysplasias caused by pathogenic variants in several genes. Here we characterize a distinct form of skeletal dysplasia in 4 individuals from 3 unrelated Emirati families. Through whole exome sequencing, we identify a novel homozygous missense variant (c.1376A>C; p.Asn459Thr) in the UFM1-specific protease 2 (UFSP2) gene segregating with disease in all affected individuals who did not have other genetic causes of disease. The UFSP2 gene encodes a cysteine protease that cleaves the C-terminal extension of Ubiquitin-fold modifier 1 (UFM1), a ubiquitin-like protein (Kang et al., 2007), which is crucial for cellular homeostasis and protein stability. Although two heterozygous pathogenic variants affecting the C-terminal catalytic domain of UFSP2 have been previously associated with two entities of skeletal dysplasia, namely Beukes hip dysplasia (BHD) and SEMD type Di Rocco (SEMDDR), the distinct clinical presentation and the biallelic inheritance in our cohort support a novel form of skeletal dysplasia. The four Emirati patients (average age: 4 years; range: 2 – 7 years) had severe disproportionate short stature (-3.5 and -4.9SD), normal head circumference, wide-based gait, bowed legs, abnormal narrow bell-shape rib cage, scoliosis with exaggerated lumbar lordosis. All patients had unremarkable intellectual and cognitive development. Their blood investigations showed a normal bone profile of serum calcium, phosphate, Alkaline phosphatase, PTH, and total vitamin D levels. Their radiological studies demonstrated metaphyseal chondrodysplasia changes mainly at the distal ends of long bones. The p.Asn459Thr missense variant has not been previously reported in individuals with the disease and was absent from large population studies such as the Genome Aggregation database v4 (gnomAD), which contains whole genome and exome sequencing data from >730,000 individuals, including >3,000 from the Middle East. Computational prediction tools and conservation analysis strongly suggest an impact of this variant on protein function. We have generated a knock-in cell line and an animal model (Zebrafish) to further characterize the cellular, biochemical, and in vivo effect of this variant and establish its pathogenic role. In summary, we report a novel form of skeletal dysplasia caused by a biallelic Emirati founder mutation in the UFSP2 gene. This work underscores the importance of UFM1 signaling in skeletal development, providing new insights into the molecular mechanisms underlying skeletal dysplasia and potential targets for therapeutic intervention.