A Novel Homozygous Synonymous Variant in CCDC134 as a Cause of Osteogenesis Imperfecta Type XXII

ABSTRACT Osteogenesis imperfecta (OI) is a heterogeneous group of rare, inherited connective tissue disorders. It includes over 20 defined subtypes, each of which is associated with distinct causative genes that are listed in the Online Mendelian Inheritance in Man (OMIM) database. Type XXII OI (OI 22) is caused by a homozygous variant in the coiled‐coil domain containing 134 ( CCDC134 ) gene, which is located on chromosome 22q13. OI, which is associated with CCDC134, is extremely rare with only five cases reported worldwide. All known cases involve the c.2 T > C (p. Met1Thr) homozygous missense variant in the CCDC134 gene. We present the case of a 13‐year‐old Chinese girl with non‐union fracture, short stature and specific radiographic findings, which include scoliosis, pelvic tilt, thin clavicles, ribs, and limbs. Whole exome sequencing revealed a novel, homozygous c.492G > C (p. Leu164=) variation in the CCDC134 gene. RNA sequencing (RNA‐seq) analysis identified this variant as an abnormal splicing variant that causes the deletion of Exon 5, which result in the observed disease phenotype. This case demonstrates the clinical phenotype of OI 22 associated with the c.492G > C (p. Leu164=) novel synonymous variation in the coding region of the CCDC134 gene in a female patient. This is the first reported case of OI 22 in the Chinese population, the sixth reported worldwide and the fourth reported genotype for diseases associated with a CCDC134 variant. It also enriches the global clinical phenotype spectrum of OI 22 patients.