IFT140 – Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder, typically driven by PKD1 and PKD2 variants. Recent reports implicate monoallelic loss-of-function variants in IFT140 as a rare cause of ADPKD (PMID:39015124; PMID:37844724). This summary evaluates the genetic and experimental evidence supporting a definitive gene–disease relationship between IFT140 and Autosomal Dominant Polycystic Kidney Disease.

Genetic evidence derives from multiple cohorts: six unrelated probands with heterozygous IFT140 frameshift variants presented with renal cysts and hypertension (PMID:37844724), 14 index cases harboring distinct IFT140 loss-of-function alleles in a 218-patient cystic nephropathy cohort (PMID:40428294), and a case series of 75 individuals from 61 families with monoallelic predicted LoF IFT140 variants (PMID:39732359). Segregation analysis across these studies identified 14 additional affected relatives, confirming autosomal dominant inheritance and co-segregation of IFT140 alleles. A representative variant is c.1377G>A (p.Trp459Ter).

The variant spectrum in ADPKD-IFT140 includes predominantly protein-truncating changes: 122 unique LoF alleles comprising 46% frameshift, 31% nonsense, 18% splice-site, and 5% exon-level deletions (PMID:39136524). A recurrent exon-13 deletion was also observed in a pediatric case and mother pair (PMID:39015124). No founder alleles have been defined, consistent with the broad allelic heterogeneity.

Functional studies support haploinsufficiency as the likely pathogenic mechanism. Affinity purification–mass spectrometry demonstrated that a subset of IFT140 missense mutations reduces IFT-A complex interactions in vitro, indicating compromised ciliary transport (PMID:39880085). Patient-derived renal epithelial cells harboring LoF IFT140 variants accumulate IFT88 at ciliary tips, reflecting retrograde trafficking defects (PMID:30479745). These cellular phenotypes parallel cystic changes in human carriers.

Clinically, ADPKD-IFT140 patients exhibit atypical bilateral kidney cysts with large exophytic lesions, limited liver involvement, mild proteinuria (HP:0012595) and hypertension (HP:0000822), and occasional hyperuricemia (HP:0002149) (PMID:40428294). Most maintain preserved glomerular filtration with rare progression to end-stage kidney disease (HP:0003774). Estimated genetic prevalence is 19.8–27.9 per 10,000 in population databases (PMID:39732359).

No conflicting reports dispute the association. Given replication across >368 probands, segregation in multiple families, and concordant functional assays, the IFT140–ADPKD link meets criteria for a Definitive ClinGen gene–disease classification. IFT140 should be included in ADPKD testing panels to improve diagnosis and guide management. Key Take-home: Monoallelic IFT140 loss-of-function variants cause a mild, atypical form of ADPKD with favorable prognosis, warranting targeted genetic screening.

References

• Case reports in nephrology and dialysis • 2024 • The First Pediatric Case of an IFT140 Heterozygous Deletion Causing Autosomal Dominant Polycystic Kidney Disease: Case Report. PMID:39015124
• American Journal of Kidney Diseases • 2024 • Monoallelic Loss-of-Function IFT140 Pathogenic Variants Cause Autosomal Dominant Polycystic Kidney Disease: A Confirmatory Study With Suspicion of an Additional Cardiac Phenotype. PMID:37844724
• Genes • 2025 • Clinical Relevance of IFT140 Loss-of-Function Variants in Development of Renal Cysts. PMID:40428294
• American Journal of Kidney Diseases • 2025 • Clinical Spectrum and Prognosis of Atypical Autosomal Dominant Polycystic Kidney Disease Caused by Monoallelic Pathogenic Variants of IFT140. PMID:39732359
• American Journal of Medical Genetics Part A • 2024 • Heterozygous loss of function variants in IFT140 are associated with polycystic kidney disease. PMID:39136524
• Cilia • 2018 • Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer-Saldino syndrome diagnosis. PMID:30479745
• Molecular & Cellular Proteomics • 2025 • Ciliopathy-Associated Missense Mutations in IFT140 are Tolerated by the Inherent Resilience of the IFT Machinery. PMID:39880085

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