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The association between CCDC134 (HGNC:26185) and osteogenesis imperfecta (MONDO_0019019) is supported by multiple independent lines of evidence. Several case reports have identified homozygous variants in CCDC134, most notably the recurrent c.2T>C (p.Met1Thr) variant, in patients presenting with severe bone fragility, blue sclerae, dentinogenesis imperfecta, short stature, scoliosis, and thin clavicles (PMID:35019224, PMID:39623602). In one study, a Brazilian boy with features of severe osteogenesis imperfecta was described carrying this translation start site variant, recapitulating findings originally reported in three families of Moroccan origin (PMID:35019224).
Additional genetic evidence arises from a separate case where a novel homozygous synonymous variant, c.492G>C (p.Leu164=), was identified. Although synonymous, RNA sequencing confirmed that this variant resulted in abnormal splicing with the deletion of exon 5, thereby establishing its pathogenic significance in the context of osteogenesis imperfecta type XXII (PMID:39623602).
Supporting these clinical observations, a multi‐patient study further documented the presence of the homozygous c.2T>C (p.Met1Thr) variant in patients from two unrelated families. This study provided critical segregation data as well as molecular validation, including the demonstration of absent CCDC134 protein expression and subsequent dysregulation of the RAS/MAPK signaling pathway. The functional assays revealed increased Erk1/2 phosphorylation alongside reduced COL1A1 expression and impaired osteoblast mineralization, thereby mechanistically linking CCDC134 loss‐of‐function to the osteogenesis imperfecta phenotype (PMID:32181939).
Collectively, the genetic data—from distinct variant types and replicative case series—and the consolidated functional evidence strongly support a causative role for CCDC134 in an autosomal recessive form of severe osteogenesis imperfecta. The evidence encompasses at least seven probands across independent studies with concordant phenotypes and robust mechanistic insights.
The integration of case reports, segregation analyses, and detailed functional assessments exceeds the ClinGen threshold for a strong association. Although additional studies may provide further depth, the current data provide a high level of confidence for clinical diagnostic decision‑making and potential therapeutic exploration using targeted RAS/MAPK inhibitors.
Key Take‑home sentence: The robust genetic and functional evidence establishes CCDC134 as a critical gene in autosomal recessive osteogenesis imperfecta, underscoring its diagnostic and therapeutic utility.
Gene–Disease AssociationStrongMultiple independent case reports totaling at least 7 probands across distinct families, with concordant clinical presentations and segregation data, support a strong gene‐disease association (PMID:35019224, PMID:39623602). Genetic EvidenceStrongThe identification of recurrent homozygous variants including c.2T>C (p.Met1Thr) and a novel synonymous c.492G>C (p.Leu164=) across multiple unrelated probands confirms the autosomal recessive inheritance and provides robust genetic support. Functional EvidenceModerateFunctional studies reveal absent CCDC134 protein, increased Erk1/2 phosphorylation, and decreased COL1A1 expression in patient-derived cells, providing mechanistic insight into the osteogenesis imperfecta phenotype (PMID:32181939). |