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.

最近在具有常染色体显性多囊肾病的非典型临床表现的七个家系中描述了DNAJB11的单等位基因突变。DNAJB11编码内质网伴侣 BiP 的主要辅助因子之一，BiP 是一种有效蛋白质折叠和运输所需的热休克蛋白。在这里，我们进行了一项国际合作研究，以更好地表征DNAJB11-相关表型。通过靶向下一代测序、全外显子组测序或全基因组测序，在 20 个新家系（54 个受影响的个体）中鉴定出 13 种不同的功能丧失变异。在目前总共报告的 77 名患者（27 个家系）中，32 名达到终末期肾病（范围，55-89 岁，中位年龄 75 岁）；男女之间无显着差异。虽然大多数患者表现为非增大的多囊肾，但在 45 岁以下的患者中肾囊肿的鉴定结果不一致。血管表型，包括颅内动脉瘤、胸主动脉扩张和颈动脉夹层，存在于四个家系中。我们访问了 Genomics England 100,000 基因组项目数据，并确定了DNAJB11的致病变异在 3934 名先证者中有 9 名患有各种肾脏和泌尿道疾病。8 例先证者临床诊断为囊性肾病，1 例先证者为肾钙质沉着症。没有发现可能解释肾脏疾病的其他致病变异。使用公开可用的 GnomAD 数据库，计算得出DNAJB11遗传流行率为 0.85/10.000 人。因此，对非典型囊性或间质性肾病进行精确诊断至关重要，对随访、遗传咨询、预后评估、治疗管理和活体肾脏供体的选择具有重要意义。