Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease (ADPKD). 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 twenty new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients ( 27pedigrees) now in total reported, 32 reached ESRD (range, 55-89y), with a median age of 75 years (0.95 CI, 72.5-77.5 years), and 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 <45y. 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 9/3934 probands with various renal and urinary tracts disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband; no additional pathogenic variants likely explaining the renal disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals (0.95 CI, 0.34-2.02). Establishing a precise diagnosis in atypical cystic or interstitial nephropathies is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for the selection of living kidney donors.
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