TY - JOUR
T1 - Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype
AU - Genomics England Research Consortium, the HALT PKD, CRISP, DIPAK, ADPKD Modifier, and TAME PKD studies
AU - Senum, Sarah R.
AU - Li, Ying (Sabrina) M.
AU - Benson, Katherine A.
AU - Joli, Giancarlo
AU - Olinger, Eric
AU - Lavu, Sravanthi
AU - Madsen, Charles D.
AU - Gregory, Adriana V.
AU - Neatu, Ruxandra
AU - Kline, Timothy L.
AU - Audrézet, Marie Pierre
AU - Outeda, Patricia
AU - Nau, Cherie B.
AU - Meijer, Esther
AU - Ali, Hamad
AU - Steinman, Theodore I.
AU - Mrug, Michal
AU - Phelan, Paul J.
AU - Watnick, Terry J.
AU - Peters, Dorien J.M.
AU - Ong, Albert C.M.
AU - Conlon, Peter J.
AU - Perrone, Ronald D.
AU - Cornec-Le Gall, Emilie
AU - Hogan, Marie C.
AU - Torres, Vicente E.
AU - Sayer, John A.
AU - Harris, Peter C.
N1 - Publisher Copyright:
© 2021 American Society of Human Genetics
PY - 2022/1/6
Y1 - 2022/1/6
N2 - 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.
AB - 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.
KW - ADPKD
KW - IFT140
KW - cilia
KW - ciliopathy
KW - intraflagellar transport
KW - monoallelic cystic disease
KW - polycystic kidney disease
KW - short rib thoracic dysplasia
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U2 - 10.1016/j.ajhg.2021.11.016
DO - 10.1016/j.ajhg.2021.11.016
M3 - Article
C2 - 34890546
AN - SCOPUS:85122023415
SN - 0002-9297
VL - 109
SP - 136
EP - 156
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -