OFD1 – Retinitis Pigmentosa

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration leading to nyctalopia and color vision defects. The oral-facial-digital syndrome 1 gene OFD1 is located on Xp22 and encodes a centrosomal protein essential for ciliogenesis. Although OFD1 is classically linked to syndromic ciliopathies, emerging reports implicate hemizygous OFD1 variants in an X-linked recessive form of RP (MONDO:0019200). Affected males present with night blindness (HP:0000662) and tritanomaly (HP:0000552), consistent with rod-cone dysfunction.

Genetic evidence arises from multiple independent case reports. A hemizygous missense variant c.358A>G (p.Thr120Ala) was identified in a male from a consanguineous pedigree with isolated RP; the variant segregated with disease in the index case (PMID:29843741). A second sporadic 6-year-old boy with RP and optic neuritis harbored an OFD1 G985S substitution, though pathogenicity remains uncertain (PMID:28191358).

A targeted sequencing study in X-linked RP23 patients uncovered a deep intronic variant, c.935+706A>G, creating a novel splice donor that inserts a cryptic exon between exons 9 and 10. Patient-derived RNA showed an aberrant transcript with frameshift p.Asn313fsTer330 and a 61% reduction in correctly spliced OFD1, indicating a hypomorphic allele compatible with male viability (PMID:22619378).

To date, three unrelated hemizygous individuals with OFD1 variants and isolated RP have been reported (3 probands ([PMID:28191358]; [PMID:29843741]; [PMID:22619378])). No multi-generation segregation beyond the index cases has been documented. All variants are absent or rare in population databases and affect splicing or conserved residues.

Functional assays support a loss-of-function mechanism. The c.935+706A>G variant demonstrated cryptic exon inclusion and reduced transcript levels in vivo. This partial loss of OFD1 in photoreceptors recapitulates a rod-cone dystrophy phenotype, paralleling findings in other ciliopathy genes where reduced dosage causes isolated retinal degeneration.

Overall, the current evidence supports a Limited gene–disease association based on three hemizygous RP cases with minimal segregation and concordant functional data. Additional replication in independent pedigrees and animal or cellular models will strengthen clinical validity. Key take-home: OFD1 should be considered in X-linked RP genetic testing panels, and intronic regions warrant evaluation for cryptic splice variants.

References

• Case reports in ophthalmological medicine • 2017 • Retinitis Pigmentosa and Bilateral Idiopathic Demyelinating Optic Neuritis in a 6-Year-Old Boy with OFD1 Gene Mutation. PMID:28191358
• Journal of translational medicine • 2018 • Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees. PMID:29843741
• 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

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