Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

• Published in: American journal of human genetics Vol. 109; no. 1; pp. 136 - 156
• Main Authors: Senum, Sarah R., Li, Ying (Sabrina) M., Benson, Katherine A., Joli, Giancarlo, Olinger, Eric, Lavu, Sravanthi, Madsen, Charles D., Gregory, Adriana V., Neatu, Ruxandra, Kline, Timothy L., Audrézet, Marie-Pierre, Outeda, Patricia, Nau, Cherie B., Meijer, Esther, Ali, Hamad, Steinman, Theodore I., Mrug, Michal, Phelan, Paul J., Watnick, Terry J., Peters, Dorien J.M., Ong, Albert C.M., Conlon, Peter J., Perrone, Ronald D., Cornec-Le Gall, Emilie, Hogan, Marie C., Torres, Vicente E., Sayer, John A., Harris, Peter C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-01-2022; Elsevier (Cell Press); Elsevier
• Subjects: ADPKD; Adult; Aged; Alleles; Amino Acid Substitution; Biological Specimen Banks; Carrier Proteins; cilia; Cilia - pathology; ciliopathy; DNA Copy Number Variations; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; IFT140; intraflagellar transport; Kidney Function Tests; Life Sciences; Male; Middle Aged; monoallelic cystic disease; Mutation; Pedigree; Phenotype; polycystic kidney disease; Polycystic Kidney, Autosomal Dominant - diagnosis; Polycystic Kidney, Autosomal Dominant - genetics; Sequence Analysis, DNA; short rib thoracic dysplasia; United Kingdom; Whole Exome Sequencing; United Kingdom; ADPKD; IFT140; polycystic kidney disease; cilia; short rib thoracic dysplasia; monoallelic cystic disease; intraflagellar transport; ciliopathy
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2021.11.016

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.
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