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Oculofaciocardio-dental (OFCD) syndrome (MONDO:0010261) is an X-linked dominant disorder characterized by microphthalmia, congenital cataracts, dental radiculomegaly, and septal heart defects. Heterozygous loss-of-function variants in the BCL-6 corepressor gene BCOR underlie OFCD, with presumed male lethality and skewed X-inactivation in females driving variable expressivity (PMID:15004558).
Genetic evidence spans over 80 unrelated patients from more than 20 pedigrees, including multigenerational cohorts with de novo and familial frameshift or nonsense mutations. Initial reports identified the hypomorphic missense variant c.254C>T (p.Pro85Leu) in male Lenz microphthalmia and null alleles in OFCD pedigrees (PMID:15004558). Subsequent case series described novel heterozygous frameshifts such as c.2326del (p.His776IlefsTer10) and c.1296del (p.Thr433ProfsTer9) segregating with dental and cardiac anomalies across three generations (PMID:22983184; PMID:30267259).
Segregation analyses have documented at least 15 additional affected female relatives carrying BCOR truncating variants with complete or highly skewed X-inactivation (PMID:19449433). Penetrance is complete for core features, while expressivity varies by generation and X-chromosome mosaicism.
The variant spectrum is dominated by premature termination codons: >50 unique frameshift, nonsense, and splice-site mutations have been reported. A recurrent de novo nonsense allele c.4540C>T (p.Arg1514Ter) has been described in unrelated families, suggesting mutational hotspots within BCOR’s functional domains (PMID:22301464). Hypomorphic missense alleles are linked to a distinct male-lethal phenotype.
Functional studies confirm BCOR’s role in transcriptional repression and epigenetic regulation. Zebrafish bcor knockdown recapitulates ocular and craniofacial anomalies, and BCOR-deficient mesenchymal stem cells show increased osteo-dentinogenic potential via AP-2α upregulation (PMID:15004558; PMID:19578371). Patient-derived periodontal ligament cells exhibit nonsense-mediated mRNA decay (NMD) of mutant transcripts and hyperproliferation, linking BCOR loss to radiculomegaly (PMID:24694763). iPSC models from OFCD patients maintain mutant-only BCOR expression and support disease modeling (PMID:31775564).
Mechanistically, BCOR haploinsufficiency disrupts a noncanonical PRC1.1 complex, leading to derepression of developmental targets and perturbation of BMP2 signaling in dental and cardiac lineages. NMD of PTC-containing transcripts further exacerbates loss of repressor activity, consistent with female-only manifestation.
Clinical integration of genetic testing for BCOR variants is critical for early diagnosis of OFCD, guiding cardiac surveillance and orthodontic management. Prenatal and preimplantation genetic diagnosis can be offered in families with known pathogenic alleles.
Key take-home: BCOR loss-of-function variants cause a definitive X-linked dominant OFCD syndrome in females, with robust genetic and functional evidence supporting clinical utility for diagnosis and management.
Gene–Disease AssociationDefinitiveMultiple independent families (>80 affected females across >20 pedigrees over 20 years), consistent segregation and functional concordance Genetic EvidenceStrong
Functional EvidenceStrongZebrafish knockdown recapitulates developmental defects; patient-derived cell models show NMD and rescue; PRC1.1 complex disruption assays |