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Abstract: TH-PO378

Monoallelic IFT140 Variants and Atypical Cystic Kidney Disease in the 100,000 Genomes Project

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Olinger, Eric Gregory, Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • Neatu, Ruxandra, Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • Wilson, Ian J., Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
  • Sayer, John Andrew, Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Background

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive kidney cysts and is an important cause for kidney failure. ADPKD is genetically heterogeneous and most commonly caused by mutations in PKD1 and PKD2. However, ~5% of families remain without a molecular diagnosis. Monoallelic variants in IFT140 have been recently described in atypical ADPKD and large databases are instrumental for a better description of this new disease entity.

Methods

Whole genome sequencing (WGS) in the context of the Genomics England 100,000 Genomes Project (100kGP) was carried out in 64,185 subjects, including 1,291 probands with cystic kidneys. This research was made possible through access to the data and findings generated by the 100kGP (www.genomicsengland.co.uk).

Results

We report a 28-year-old man with PKD1/2-negative cystic kidneys and recruited into the 100kGP. A review of his imaging revealed an atypical pattern of kidney cysts (Figure) and he was noted to have preserved kidney function and normotension. Of his two children one had kidney cysts aged 8 years. WGS data revealed a heterozygous predicted loss of function (pLOF) variant in IFT140 in the index patient and his affected child. Analysis of 100kGP data identified 26 pLOF variants in a total of 152 individuals from 111 different families. Among these 152 individuals, kidney cyst(s) were described in 38 individuals (25%), CKD in only 7 (5%) and kidney failure in 6 individuals (4%). Overall, 26 out of 1,291 (2%) probands with cystic kidney disease as their primary recruitment groups had IFT140 pLOF variants. Mean age at diagnosis was 48.4±18.1 years. Only ICD term Q61 (cystic kidney disease) showed phenome-wide significant association with IFT140 monoallelic pLOF variants (p=2.9x10-9, OR=5.6 (3.3-9.2)).

Conclusion

IFT140 pLoF variants are an important cause of atypical ADPKD without apparent extrarenal manifestations and should be considered in PKD1/2-negative patients, especially those with mild clinical course and preserved kidney function.

Figure: Abdominal CT showing few large kidney cysts