1. Am J Kidney Dis. 2024 Dec 26:S0272-6386(24)01126-0. doi: 
10.1053/j.ajkd.2024.10.009. Online ahead of print.

Clinical Spectrum and Prognosis of Atypical Autosomal Dominant Polycystic Kidney 
Disease Caused by Monoallelic Pathogenic Variants of IFT140.

Zagorec N(1), Calamel A(1), Delaporte M(1), Olinger E(2), Orr S(3), Sayer JA(4), 
Pillay VG(5), Denommé-Pichon AS(5), Mau-Them FT(5), Nambot S(6), Faivre L(7), 
Ars E(8), Torra R(9), Ong AC(10), Devuyst O(11), Perico N(12), Després AM(1), 
Lemoine H(13), de Fallois J(14), Brousse R(15), Hummel A(16), Knebelmann B(16), 
Maisonneuve N(17), Halbritter J(18), Le Meur Y(19), Audrézet MP(20), Cornec-Le 
Gall E(21); Genomics England Research Consortium, CYSTic Consortium and Genkyst 
Study Group.

Author information:
(1)Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre de 
référence MARHEA, CHRU Brest, Brest, France.
(2)Center for Human Genetics, Cliniques Universitaires Saint-Luc, UCLouvain, 
Brussels, Belgium.
(3)Biosciences Institute, Newcastle University, Central Parkway, Newcastle Upon 
Tyne, United Kingdom.
(4)Biosciences Institute, Newcastle University, Central Parkway, Newcastle Upon 
Tyne, United Kingdom; The Newcastle upon Tyne Hospitals NHS Foundation Trust, 
Renal Services, Freeman Road, Newcastle Upon Tyne, United Kingdom; NIHR 
Newcastle Biomedical Research Centre, Newcastle University, Newcastle Upon Tyne, 
United Kingdom.
(5)Unité Fonctionnelle Innovation en Diagnostic Génomique des maladies rares, 
CHU Dijon Bourgogne, Dijon, France.
(6)INSERM UMR1231 GAD, Genetics of Developmental Disorders, Université de 
Bourgogne-Franche-Comté, Dijon, France.
(7)INSERM UMR1231 GAD, Genetics of Developmental Disorders, Université de 
Bourgogne-Franche-Comté, Dijon, France; Centre de Génétique et Centre de 
Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion 
Est, Centre Hospitalier Universitaire Dijon, Dijon, France; Fédération 
Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement 
(TRANSLAD), CHU Dijon, Dijon, France.
(8)Molecular Biology Laboratory, Fundació Puigvert, Instituto de Recerca Sant 
Pau (R Sant Pau), RICORS2040, Barcelona, Spain.
(9)Department of Nephrology, Fundació Puigvert, Instituto de Recerca Sant Pau (R 
Sant Pau), Universitat Autónoma de Barcelona, Medicine Department, RICORS2040, 
Barcelona, Spain.
(10)Kidney Genetics Group, Academic Nephrology, Division of Clinical Medicine, 
School of Medicine and Population Health, University of Sheffield, Sheffield, 
UK; Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation 
Trust, Sheffield, UK.
(11)Institute of Physiology, University of Zurich, Zurich, Switzerland.
(12)Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
(13)Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, 
Belgium.
(14)Service de Génétique moléculaire, CHRU Brest, Brest, France.
(15)University of Brest, Inserm, UMR 1078, Génétique, Génomique fonctionelle et 
Biotechnologies, Brest, France.
(16)Division of Nephrology, Department of Internal Medicine, University of 
Leipzig Medical Center, Leipzig, Germany.
(17)Sorbonne Université, INSERM UMRS 1155, Nephrology Department, Assistance 
Publique Hopitaux De Paris, Hopital Tenon, Paris, France.
(18)Department of Nephrology, Necker Hospital, Assistance Publique-Hopitaux de 
Paris, Paris, France.
(19)Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre de 
référence MARHEA, CHRU Brest, Brest, France; Service de Néphrologie-Dialyse, 
Centre Hospitalier de Valenciennes, Valenciennes, France.
(20)Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; 
Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, 
Belgium.
(21)Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre de 
référence MARHEA, CHRU Brest, Brest, France; Institut de Recherche Expérimentale 
et Clinique (IREC), UCLouvain, Brussels, Belgium. Electronic address: 
emilie.cornec-legall@chu-brest.fr.

RATIONALE & OBJECTIVE: Monoallelic predicted Loss-of-Function (pLoF) variants in 
IFT140 have recently been associated with an autosomal dominant polycystic 
kidney disease (ADPKD)-like phenotype. This study sought to enhance the 
characterization of this phenotype.
STUDY DESIGN: Case series.
SETTING & PARTICIPANTS: Seventy-five among 2797 European individuals with 
ADPKD-like phenotypes who underwent genetic testing that revealed pLoF 
IFT140-variants.
FINDINGS: The 75 individuals (median age 56 years, 53.3% females) were from 61 
families and were found to have 41 different monoallelic pLoF IFT140-variants. 
The majority of individuals presented with large, exophytic kidney cysts (median 
[range] total kidney volume 688 ml [201-4139]), and 90.2% were classified using 
the Mayo Imaging Classification as Mayo Class 2A. Arterial hypertension was 
present in 50.7% of the individuals (median [range] age at diagnosis 59 years 
[29-73]). Only one patient developed kidney failure (at age 69 years). A 
significant difference in age-adjusted eGFR between male and female patients was 
observed (P<0.001). 56.3% of the individuals over the age of 60 years had an 
eGFR less than 60ml/min/1.73m2. The estimated genetic prevalence of monoallelic 
pLoF IFT140 variants was 19.76 (95%CI=18.8-20.7) and 27.89 (95%CI=23.8-31.9) per 
10,000 in the Genome Aggregation Database and the 100,000 Genomes Project 
(100kG), respectively. CyKD (ICD-10 Q61) was associated with pLoF IFT140 
variants (P=2.9x10-9, OR=5.6 (3.3-9.2)) only in 100kG.
STUDY LIMITATIONS: Retrospective study; younger patients and patients with 
milder forms of IFT140-related CyKD may not be diagnosed.
CONCLUSIONS: Individuals with monoallelic IFT140 pLoF variants are likely to 
develop kidney cysts atypical of classical ADPKD and generally have a favorable 
kidney prognosis.

Copyright © 2024. Published by Elsevier Inc.

DOI: 10.1053/j.ajkd.2024.10.009
PMID: 39732359