IFT140 – Retinitis Pigmentosa

Pathogenic biallelic variants in IFT140 have been repeatedly identified in patients with non-syndromic retinitis pigmentosa (RP), defining an autosomal recessive retinal dystrophy characterized by rod–cone degeneration without extraretinal ciliopathy features. An initial exome and targeted panel screen in five unrelated families (eight affected individuals) uncovered compound heterozygous and homozygous IFT140 variants, with two novel alleles c.2815T>C (p.Ser939Pro) and c.1422_23insAA (p.Arg475Asnfs*14), all segregating with RP (mean age at diagnosis 42 years) and lacking skeletal or renal involvement (PMID:26968735).

Independent retinal capture and whole-exome sequencing in multiple unrelated LCA and RP cohorts validated IFT140 as a non-syndromic retinal degeneration gene, identifying rare predicted-damaging splice-site and frameshift alleles (e.g., c.1653-2A>G, c.167del (p.Thr56fs)) with full segregation in available families (PMID:26216056). A recent single‐patient chart review described a 42-year-old male with RP and spermatogenic dysfunction harboring two IFT140 variants, reinforcing the retinal specificity of IFT140 in the absence of skeletal ciliopathy signs (PMID:38084016).

Across studies, IFT140 variant classes include missense (e.g., c.2815T>C (p.Ser939Pro)), splice-site, frameshift and nonsense changes, with no recurrent founder alleles in RP cohorts. Patients uniformly exhibit preserved visual acuity into mid‐adult life and no systemic ciliopathy stigmata, underscoring a restricted retinal phenotype despite IFT140’s broader role in intraflagellar transport.

Functional assays in hTERT-RPE1 cells demonstrate that nonsyndromic RP–associated IFT140 missense alleles significantly reduce basal body localization of the IFT140 protein compared to wild type, confirming a loss of ciliary transport function concordant with photoreceptor degeneration (PMID:26968735).

No studies have refuted the IFT140–RP link. Together, genetic and experimental data satisfy ClinGen criteria for a strong gene‐disease association, guiding molecular diagnosis and genetic counseling for autosomal recessive RP.

Key Take-home: Biallelic IFT140 variants cause a distinct non-syndromic autosomal recessive retinitis pigmentosa through impaired intraflagellar transport in photoreceptors.

References

• Investigative ophthalmology & visual science • 2016 • Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140. PMID:26968735
• Human genetics • 2015 • Mutations in human IFT140 cause non-syndromic retinal degeneration. PMID:26216056
• Ophthalmic genetics • 2024 • Male infertility may be associated with IFT140-related autosomal recessive retinitis pigmentosa. PMID:38084016

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