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 - Funding Information:
We thank the families and coordinators for involvement in the study and Saurabh Baheti (Mayo Clinic), Dana Miskulin (Tufts University), Susan L. Murray (Beaumont Hospital, Dublin), Aurore Despres and Christelle Guillerm (CHU Brest), Aude Promerat and Cécile Lemoine (Roubaix), Anne-Laure Faucon (Corbeil-Essone), Emad Khazned (Bourges), Alain Michel (Saint Malo), Charles J. Blijdorp (Erasmus Medical Center, Rotterdam), Rene M.M. van Aerts (University Medical Center Radboud, Nijmegen), and Shosha E.I. Dekker (Leiden University Medical Center) for technical assistance or referring individuals. This research was conducted with data from UK Biobank (project ID 43879) and data and findings from the 100,000 Genomes Project. The study was supported by NIDDK grants DK058816 and DK059597 (P.C.H.); the Mayo Translational PKD Center (DK090728; V.E.T.); the Zell Family Foundation, Robert and Billie Kelley Pirnie, an Early Postdoc Mobility Stipendium, Swiss National Science Foundation (P2ZHP3_195181), and Kidney Research UK (Paed_RP_001_20180925) (E.O.); Kidney Research UK and the Northern Counties Kidney Research Fund (J.A.S.); a Barbour Foundation Postgraduate Research Studentship (R.P.); and Kuwait Foundation for the Advancement of Sciences (KFAS) grant PR17-13MM-07 (H.O.). The Irish Kidney Gene Project was funded by THE HEALTH RESEARCH BOARD, Irish Nephrology Society, Irish Kidney Association under the HRCI-HRB Joint Funding Scheme HRCI-HRB-2020-032; the Baltimore PKD Research and Clinical Core Center were supported by P30DK090868 and U54 DK126114. Support for HALT PKD, CRISP, the ADPKD Modifier Study, Genkyst, DIPAK, the UK Biobank, and the 100,000 Genomes Project are shown in the supplemental materials, along with additional investigators from these studies. M.M. reports grants and consulting fees outside the submitted work from Otsuka Pharmaceuticals, Sanofi, Chinook, Goldilocks, Natera, and Palladio. R.D.P. reports clinical trial support from Reata, Kadmon, Sanofi-Genzyme, US Department of Defense; consultant/advisory fees from Otsuka and Sanofi-Genzyme; and is section editor Renal Cystic Disease: UpToDate. J.A.S. has received honorarium from consulting positions from Otsuka Pharmaceuticals, Sanofi, and Takeda. V.E.T. reports grants and/or other fees from Mironid, Blueprint Medicines, Otsuka Pharmaceuticals, Palladio Biosciences, Sanofi Genzyme, Reata, and Regulus Therapeutics, all outside the submitted work.
Funding Information:
We thank the families and coordinators for involvement in the study and Saurabh Baheti (Mayo Clinic), Dana Miskulin (Tufts University), Susan L. Murray (Beaumont Hospital, Dublin), Aurore Despres and Christelle Guillerm (CHU Brest), Aude Promerat and Cécile Lemoine (Roubaix), Anne-Laure Faucon (Corbeil-Essone), Emad Khazned (Bourges), Alain Michel (Saint Malo), Charles J. Blijdorp (Erasmus Medical Center, Rotterdam), Rene M.M. van Aerts (University Medical Center Radboud, Nijmegen), and Shosha E.I. Dekker (Leiden University Medical Center) for technical assistance or referring individuals. This research was conducted with data from UK Biobank (project ID 43879) and data and findings from the 100,000 Genomes Project. The study was supported by NIDDK grants DK058816 and DK059597 (P.C.H.); the Mayo Translational PKD Center ( DK090728 ; V.E.T.); the Zell Family Foundation , Robert and Billie Kelley Pirnie , an Early Postdoc Mobility Stipendium, Swiss National Science Foundation ( P2ZHP3_195181 ), and Kidney Research UK ( Paed_RP_001_20180925 ) (E.O.); Kidney Research UK and the Northern Counties Kidney Research Fund (J.A.S.); a Barbour Foundation Postgraduate Research Studentship (R.P.); and Kuwait Foundation for the Advancement of Sciences (KFAS) grant PR17-13MM-07 (H.O.). The Irish Kidney Gene Project was funded by THE HEALTH RESEARCH BOARD , Irish Nephrology Society , Irish Kidney Association under the HRCI-HRB Joint Funding Scheme HRCI-HRB-2020-032 ; the Baltimore PKD Research and Clinical Core Center were supported by P30DK090868 and U54 DK126114 . Support for HALT PKD, CRISP, the ADPKD Modifier Study, Genkyst, DIPAK, the UK Biobank, and the 100,000 Genomes Project are shown in the supplemental materials , along with additional investigators from these studies.
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
VL - 109
SP - 136
EP - 156
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -