1. Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype
- Author
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Senum, S.R., Li, Y.M., Benson, K.A., Joli, G., Olinger, E., Lavu, S., Madsen, C.D., Gregory, A.V., Neatu, R., Kline, T.L., Audrezet, M.P., Outeda, P., Nau, C.B., Meijer, E., Ali, H., Steinman, T.I., Mrug, M., Phelan, P.J., Watnick, T.J., Peters, D.J.M., Ong, A.C.M., Conlon, P.J., Perrone, R.D., Gall, E.C.L., Hogan, M.C., Torres, V.E., Saver, J.A., Harris, P.C., Genomics England Res Consortium, HALT PKD, CRISP, DIPAK, ADPKD Modifier, TAME PKD studies, Groningen Kidney Center (GKC), Mayo Clinic [Rochester], Royal College of Surgeons in Ireland (RCSI), IRCCS San Raffaele Scientific Institute [Milan, Italie], Newcastle University [Newcastle], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), University of Maryland School of Medicine, University of Maryland System, University of Groningen [Groningen], Kuwait University, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), University of Alabama at Birmingham [ Birmingham] (UAB), Royal Infirmary of Edinburgh, Leiden University Medical Center (LUMC), The Medical School - The University of Sheffield [U.K.], Tufts University School of Medicine [Boston], and PODEUR, Sophie
- Subjects
Adult ,Male ,DNA Copy Number Variations ,[SDV]Life Sciences [q-bio] ,PKD1 ,urologic and male genital diseases ,DIAGNOSIS ,Kidney Function Tests ,DISEASE ,Article ,short rib thoracic dysplasia ,monoallelic cystic disease ,IFT140 ,Exome Sequencing ,Genetics ,Humans ,Genetic Predisposition to Disease ,Cilia ,Genetic Testing ,Genetics (clinical) ,CYST FORMATION ,Alleles ,Genetic Association Studies ,ADPKD ,Aged ,Biological Specimen Banks ,intraflagellar transport ,polycystic kidney disease ,COMPLEX ,urogenital system ,MUTATIONS ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Middle Aged ,Polycystic Kidney, Autosomal Dominant ,GENE ,female genital diseases and pregnancy complications ,RENAL CYSTS ,United Kingdom ,Pedigree ,[SDV] Life Sciences [q-bio] ,ciliopathy ,Phenotype ,Amino Acid Substitution ,Mutation ,Female ,DEFINES ,Carrier Proteins - Abstract
International audience; Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum.
- Published
- 2021
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