TY - JOUR
T1 - Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease
AU - Genkyst Study Group, Genomics England Research Consortium
AU - Huynh, Vinh T.
AU - Audrézet, Marie Pierre
AU - Sayer, John A.
AU - Ong, Albert C.
AU - Lefevre, Siriane
AU - Le Brun, Valoris
AU - Després, Aurore
AU - Senum, Sarah R.
AU - Chebib, Fouad T.
AU - Barroso-Gil, Miguel
AU - Patel, Chirag
AU - Mallett, Andrew J.
AU - Goel, Himanshu
AU - Mallawaarachchi, Amali C.
AU - Van Eerde, Albertien M.
AU - Ponlot, Eléonore
AU - Kribs, Marc
AU - Le Meur, Yannick
AU - Harris, Peter C.
AU - Cornec-Le Gall, Emilie
N1 - Funding Information:
This study was supported by a National Plan for Clinical Research (Plan Hospitalier de Recherche Clinique inter-regional GeneQuest, NCT02112136 to ECLG), National Institute of Diabetes and Digestive and Kidney Diseases grant DK058816 (PCH), the Mayo Translational PKD Center (DK090728), and Dutch Kidney Foundation grant 18OKG19 (AMVE).
Funding Information:
JAS has received speaker’s fees and consultancy honoraria from Otsuka Pharmaceutical Industry; PCH has received research grants from Otsuka Pharmaceutical and consultancy honoraria from Mitobridge and Vertex Pharma; AJM has received research grant funding from Sanofi-Genzyme and is a Medical Advisory Board member for Otsuka Australia; and EC-LG has received speaker’s fees or consultancy honoraria from Otsuka Pharmaceutical Industry, Genzyme, and MedUpdate Europe. All the other authors declared no competing interests.
Funding Information:
We thank the families and coordinators for involvement in the study. We would like to thank the nephrologists and other physicians who helped with the study: Julie Albaret, MD (Vichy, France); Franck Bridoux, MD, PhD (Poitiers, France); Fouad Chebib, MD (Rochester, MN); Lionel Couzi, MD, PhD (Bordeaux, France); Camille Domenger, MD (Poitiers, France); Laurent Doucet, MD (Brest, France); Jean-Michel Halimi, MD, PhD (Tours, France); Thierry Frouget, MD (Rennes, France); Marie Hogan, MD, PhD (Rochester, MN); Andrea Kattah, MD (Rochester, MN); Agnes La Batide-Alanore, MD (Paris, France); H?l?ne Longuet, MD (Tours, France); Pierre Paille (Roeschwoog, France); Aur?lie Pajot, MD (Angers, France); Mathilde Prezelin-Reydit, MD (Bordeaux, France); Kimon Runge, MD (Freiburg, Germany); Guillaume Seret, MD (Le Mans, France); and Vicente Torres, MD, PhD (Rochester, MN). We would like to acknowledge the study coordinators Christelle Guillerm-Regost, Christelle Ratajczak, and No?e Gales (Brest, France), Fabien Duthe (Poitiers, France), and Charles Madsen (Rochester, MN). This study was supported by a National Plan for Clinical Research (Plan Hospitalier de Recherche Clinique inter-regional GeneQuest, NCT02112136 to ECLG), National Institute of Diabetes and Digestive and Kidney Diseases grant DK058816 (PCH), the Mayo Translational PKD Center (DK090728), and Dutch Kidney Foundation grant 18OKG19 (AMVE). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council also have funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.
Publisher Copyright:
© 2020 International Society of Nephrology
PY - 2020/8
Y1 - 2020/8
N2 - Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.
AB - Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.
KW - DNAJB11
KW - chronic kidney disease
KW - genetics
KW - polycystic kidney disease
KW - prognosis
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U2 - 10.1016/j.kint.2020.02.022
DO - 10.1016/j.kint.2020.02.022
M3 - Article
C2 - 32631624
AN - SCOPUS:85082874556
VL - 98
SP - 476
EP - 487
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 2
ER -