Monoallelic Loss-of-Function IFT140 Pathogenic Variants Cause Autosomal Dominant Polycystic Kidney Disease: A Confirmatory Study With Suspicion of an Additional Cardiac Phenotype

Am J Kidney Dis. 2024 May;83(5):688-691. doi: 10.1053/j.ajkd.2023.08.019. Epub 2023 Oct 14.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. While biallelic variants affecting IFT140 are responsible for Mainzer-Saldino syndrome (characterized by severe ciliopathy causing skeletal abnormalities, kidney disease, and cysts), monoallelic loss-of-function (LoF) variants have been recently reported as an important cause of ADPKD beyond PKD1/2 genes. Herein, we report 6 non-family-related cases of monoallelic IFT140 LoF variants, identified from 1,340 exomes sequenced for nephrological indications in our local database. Every patient presented with polycystic kidney disease. Furthermore, the mother of a boy diagnosed with Mainzer-Saldino syndrome with a biallelic variant affecting IFT140 presented with several bilateral cysts, revealed after kidney imaging, and was found to carry a pathologic frameshift IFT140 variation. As well as this particular Mainzer-Saldino case, our 6 additional patients confirm that heterozygous IFT140 frameshift variants are responsible for the cystic phenotype and kidney failure. Interestingly, of the 6 patients, 2 also exhibited dilated cardiomyopathy, which was of unknown origin, as no genetic cause was found after exome sequencing analysis, suggesting a potential connection between IFT140 and heart disease.

Keywords: kidney cyst, chronic renal failure, cardiopathy, genetic disease.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Cardiomyopathy, Dilated / genetics
  • Carrier Proteins* / genetics
  • Child
  • Female
  • Frameshift Mutation
  • Humans
  • Loss of Function Mutation*
  • Male
  • Pedigree
  • Phenotype
  • Polycystic Kidney, Autosomal Dominant* / complications
  • Polycystic Kidney, Autosomal Dominant* / diagnosis
  • Polycystic Kidney, Autosomal Dominant* / genetics

Substances

  • Carrier Proteins
  • IFT140 protein, human