A Novel Homozygous Missense Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies with or without Cardiac Anomalies 2.

INTRODUCTION

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 is a very rare genetic disorder caused by biallelic pathogenic variants in the gene and has been reported in approximately 20 patients to date. SCUBE3 protein exhibits significant expression in various tissues, including primary osteoblasts, long bones, and the cartilage of the axial skeleton throughout development, while also playing a regulatory role in the FGF, Hedgehog, and TGF-β signaling pathways.

CASE PRESENTATION

We report a 13-year-old female patient from a consanguineous Turkish family with a novel homozygous missense variant, c.908G>C (p.Cys303Ser) in the gene identified, through exome sequencing. The patient exhibited prenatal growth retardation, short stature, microcephaly, distinctive facial traits, such as long face, high arched eyebrows, epicanthus, blepharoptosis, hypotelorism, high nasal bridge, micrognathia, and large ears, dental anomalies, and skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings.

CONCLUSION

Protein modeling using AlphaFold3 revealed disruption of a critical disulfide bridge within the seventh epidermal growth factor-like repeat, likely affecting protein stability. In this study, we aimed to further characterize the clinical, radiological, and molecular features of this disorder with protein modeling.