IFT140 – Short-rib Thoracic Dysplasia 9 with or without Polydactyly

IFT140 encodes a core component of the intraflagellar transport A (IFT-A) complex required for retrograde protein trafficking in cilia. Biallelic pathogenic variants in IFT140 underlie autosomal recessive Short-rib Thoracic Dysplasia 9 with or without Polydactyly (also termed Mainzer-Saldino syndrome) (MONDO_0009964) characterized by short limbs, narrow thorax, retinal dystrophy, and progressive renal failure. Variants segregate with disease in multiple unrelated families, and functional assays demonstrate impaired retrograde IFT and rescue of ciliary defects.

Multiple unrelated probands (≈39) from ≥15 families have been reported with compound heterozygous or homozygous IFT140 variants in Short-rib Thoracic Dysplasia 9 ([PMID:22503633]). Segregation analysis across 6 families confirms autosomal recessive inheritance of biallelic loss-of-function and missense variants ([PMID:22503633]). The variant spectrum includes >80 alleles: canonical splice-site, nonsense, frameshift, and missense changes affecting conserved domains. A recurrent founder missense, c.1990G>A (p.Glu664Lys), also causes isolated congenital retinal dystrophy in several families on the Arabian Peninsula ([PMID:26359340]).

Segregation data show co-segregation of IFT140 variants with disease in 6 affected families ([PMID:22503633]). Case reports in infants and children with retinal or skeletal ciliopathy features further support pathogenicity. A series of 12 subjects homozygous for c.1990G>A exhibited early-onset retinal dystrophy, hyperopia, nystagmus, and variable extraocular involvement ([PMID:26359340]).

Functional studies in patient‐derived cells and model systems have demonstrated concordant defects in retrograde IFT. Patient urinary renal epithelial cells display accumulation of IFT-B proteins at ciliary tips in 41% of cilia, indicative of impaired retrograde transport; this phenotype is rescued by wild-type but not mutant IFT140 (p.Tyr923Asp) ([PMID:30479745]). Knockout and complementation assays establish that p.Tyr923Asp fails to restore normal IFT, confirming loss of function.

Representative variant: c.2767T>G (p.Tyr923Asp) illustrates a pathogenic missense change impairing IFT-A function in vitro and co-segregating with disease. Reclassification of variants of uncertain significance is aided by protein stability prediction (ΔΔG) and quantitative interaction assays, enhancing diagnostic yield.

Integration of robust genetic and experimental data across multiple cohorts establishes a definitive gene–disease relationship. Additional evidence from animal models and energy‐based variant analyses further supports mechanism via loss of retrograde transport. Key take-home: Genetic testing for IFT140 biallelic variants enables accurate diagnosis of Short-rib Thoracic Dysplasia 9, informs prognosis for renal and retinal involvement, and guides early monitoring and management.

References

• American Journal of Human Genetics • 2012 • Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. PMID:22503633
• Cilia • 2018 • Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer-Saldino syndrome diagnosis. PMID:30479745
• The British Journal of Ophthalmology • 2016 • The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy. PMID:26359340
• Journal of AAPOS • 2024 • Mutations in the ciliary transport gene IFT140 cause syndromic congenital retinal dystrophy. PMID:39304031

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