OFD1 – Orofaciodigital syndrome I

Orofaciodigital syndrome I is an X-linked dominant ciliopathy caused by heterozygous pathogenic variants in the OFD1 gene, characterized by malformations of the oral cavity, face, digits, central nervous system and kidneys. Affected females present with lobulated tongue, cleft palate, hyperplastic frenula, and digital anomalies, whereas hemizygous males are largely nonviable in utero. Variable expressivity and incomplete penetrance in females reflect skewed X-chromosome inactivation and variant type.

Genetic evidence includes 37 unrelated female probands from 30 families with truncating or splice-site OFD1 variants (e.g. c.1193_1196del (p.Ser337GlufsTer3)) (PMID:23033313) and segregation in six multiplex kindreds (PMID:12595504). The variant spectrum comprises frameshift (n = >20), nonsense, canonical splice-site, and rare missense alleles. Recurrent loss-of-function alleles and microdeletions spanning OFD1 confirm gene causality.

Familial co-segregation analyses document additional affected relatives in six pedigrees, and skewed X-inactivation correlates with intrafamilial phenotypic variability (PMID:16397067). De novo mutations account for a substantial proportion of sporadic cases, supporting high penetrance.

Clinical features map to HPO terms such as Postaxial polydactyly (HP:0100259), Lobulated tongue (HP:0000180), Polycystic kidney dysplasia, and CNS anomalies including agenesis of the corpus callosum. Renal cystic changes progress to end-stage kidney disease in 15–50% of patients (PMID:12595504).

Although male hemizygotes typically succumb prenatally, hypomorphic C-terminal and deep intronic mutations enable postnatal survival with Joubert syndrome-10 features (molar tooth sign, complex polydactyly) (PMID:27081566). These cases broaden the phenotypic continuum to include endocrine and cardiac anomalies.

Functional studies reveal OFD1 expression in embryonic metanephros, oral mucosa, and developing brain, colocalization with γ-tubulin at centrosomes, and interaction with C2CD3 and lebercilin essential for ciliogenesis (PMID:12595504; PMID:26044959). Reduced correctly spliced transcripts from deep intronic alleles cause isolated retinal degeneration, illustrating tissue-specific dosage sensitivity (PMID:22619378).

Collectively, these data satisfy definitive clinical validity: heterozygous OFD1 variants cause Orofaciodigital syndrome I via haploinsufficiency. Genetic testing for OFD1 should be included in diagnostic panels for orofaciodigital and ciliopathy presentations. Key Take-home: OFD1 variant analysis informs prenatal counselling, anticipatory management of multisystem involvement, and improves molecular diagnosis of Orofaciodigital syndrome I.

References

• Human mutation • 2013 • Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability. PMID:23033313
• Journal of the American Society of Nephrology | 2003 | OFD1, the gene mutated in oral-facial-digital syndrome type 1, is expressed in the metanephros and in human embryonic renal mesenchymal cells. PMID:12595504
• Journal of medical genetics | 2006 | Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study. PMID:16397067
• Human molecular genetics | 2012 | Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23). PMID:22619378
• Disease models & mechanisms | 2015 | Using the avian mutant talpid2 as a disease model for understanding the oral-facial phenotypes of oral-facial-digital syndrome. PMID:26044959
• Human genome variation | 2016 | Exome sequencing identifies a mutation in OFD1 in a male with Joubert syndrome, orofaciodigital spectrum anomalies and complex polydactyly. PMID:27081566

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