C2CD3 – Orofaciodigital syndrome type 14

Autosomal recessive biallelic variants in C2CD3 have been identified in six unrelated probands across six families, supporting a consistent inheritance model for Orofaciodigital syndrome type 14 (AR) (6 probands) ([PMID:39690811]; [PMID:30097616]; [PMID:27094867]). Exome sequencing revealed compound heterozygous missense changes in a patient with isolated nephronophthisis and classical OFD14 features, with no additional affected relatives documented. Initial reports described two families with microcephaly and cerebral malformations, while subsequent studies expanded the phenotype to include cystic kidney disease without overt craniofacial anomalies. The variant spectrum encompasses hypomorphic missense and canonical splice site alterations that co-segregate with disease under an autosomal recessive model. A recurrent hypomorphic missense allele, c.6236C>T (p.Thr2079Met), was observed in both isolated nephronophthisis and syndromic cases, underscoring allelic heterogeneity and organ-specific effects ([PMID:39690811]).

C2CD3 variant classes include missense substitutions affecting conserved C2 domains and predicted splice-disrupting intronic changes. In three pedigrees, six distinct variants (including c.5090+5G>C and c.1365+1G>A) were confirmed to alter splicing via RNA analysis, leading to truncated products and loss of function consistent with ACMG pathogenicity criteria ([PMID:30097616]). The predominant mechanism is biallelic hypomorphic dysfunction rather than complete loss, correlating with variable phenotypic severity.

Functional studies in murine C2cd3 knockouts demonstrated essential roles in ciliogenesis and Hedgehog (SHH) signaling, with embryos exhibiting neural tube defects, disrupted Gli3 processing, and basal body anomalies ([PMID:19004860]). Avian talpid2 mutants harboring a 19-bp deletion in C2CD3 recapitulate polydactyly and craniofacial clefting, implicating impaired centriole docking and GLI3 activator dysregulation in facial morphogenesis ([PMID:25053433]).

Patient-derived fibroblasts and urinary renal epithelial cells from an OFD14 case displayed significantly shortened cilia (2.309 vs. 2.850 μm in fibroblasts; 2.068 vs. 2.807 μm in URECs; p < 0.0001) and a 40.8% reduction in ciliation, accompanied by diminished GLI3 activator and GLI1 expression ([PMID:39690811]). Rescue experiments in C2CD3 knockout RPE-1 cells confirmed impaired restoration of ciliogenesis for each variant, consolidating a hypomorphic mechanism affecting SHH output in renal epithelium.

No studies to date have refuted the association; all evidence converges on autosomal recessive hypomorphic C2CD3 dysfunction as the basis for OFD14. The combination of multiple unrelated probands with co-segregation of biallelic variants and concordant in vitro and in vivo functional data meets criteria for a Strong gene-disease relationship. This establishes C2CD3 as a clinically actionable gene for diagnostic testing in patients with orofaciodigital features and cystic renal disease.

Key Take-home: Biallelic hypomorphic C2CD3 variants cause autosomal recessive Orofaciodigital syndrome type 14 by disrupting ciliogenesis and SHH signaling, supporting routine inclusion of C2CD3 in ciliopathy gene panels for craniofacial and renal phenotypes.

References

• Human molecular genetics • 2025 • Use of patient-derived cell models for characterization of compound heterozygous hypomorphic C2CD3 variants in a patient with isolated nephronophthisis. PMID:39690811
• European Journal of Human Genetics • 2018 • Characterization of three ciliopathy pedigrees expands the phenotype associated with biallelic C2CD3 variants. PMID:30097616
• Scientific Reports • 2016 • Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function. PMID:27094867
• Development (Cambridge, England) • 2008 • C2cd3 is required for cilia formation and Hedgehog signaling in mouse. PMID:19004860
• Development (Cambridge, England) • 2014 • The cellular and molecular etiology of the craniofacial defects in the avian ciliopathic mutant talpid2. PMID:25053433

Evidence Based Scoring (AI generated)