Homozygous Synonymous Variant in CCDC134 with Osteogenesis Imperfecta Type XXII in a Three-Generation Chinese Family

Background: Osteogenesis imperfecta (OI) type XXII is an ultra-rare autosomal recessive disorder caused by biallelic pathogenic variants in CCDC134 . To date, only six cases have been reported worldwide: five harboring the c.2T>C (p.Met1Thr) variant and one with the synonymous c.492G>C (p.Leu164Leu) change. We report two siblings carrying the c.492G>C variant, thereby expanding the clinical and therapeutic phenotype spectrum of this ultra-rare condition. Methods: Two siblings presenting with recurrent fractures and low bone mineral density (BMD) underwent comprehensive evaluation. Trio-based whole-exome sequencing was performed, followed by Sanger sequencing for segregation analysis. The impact of the variant on pre-mRNA splicing was assessed by reverse transcription PCR (RT-PCR) and Sanger sequencing of cDNA. Clinical, radiological, and densitometric data were collected at baseline and during follow-up after intravenous zoledronic acid therapy. Results: Both siblings were homozygous for the CCDC134 c.492G>C variant. RT-PCR and cDNA sequencing confirmed complete skipping of exon 5. The proband (11 years) exhibited multiple long-bone fractures, severe osteopenia (femoral neck Z-score = −5.0), and persistent non-union of a right femoral fracture despite three cycles of zoledronic acid, although BMD showed modest improvement. His younger sister (7 years), who was fracture-naïve at presentation, had low BMD (femoral neck Z-score = −2.9) and demonstrated a more pronounced BMD response after a single treatment cycle. Conclusions: Our findings confirm that the synonymous c.492G>C variant causes OI type XXII through exon 5 skipping and significantly broaden the clinical and therapeutic phenotype spectrum, including variable expressivity and differential responses to bisphosphonate therapy. Early initiation of treatment may improve BMD; however, established non-union appears refractory to zoledronic acid.