Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease

Abstract

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.

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

“…11,14 GANAB encodes glucosidase IIa (GIIa); pathogenic variation in its binding partner GIIb (encoded by PRKCSH [MIM: 177060]) is a common cause of ADPLD. 15,16 In contrast, DNAJB11-nephropathy is characterized by the development of small kidney cysts and fibrosis and resulting in ESKD in later life, 12,17 a phenotype related to autosomal dominant tubulointerstitial kidney disease (ADTKD [MIM: 162000]) due to UMOD (MIM: 162000) or MUC1 (MIM: 158340) pathogenic variants. 18 The ALG9 phenotype is of moderate cystic kidney disease and occasional ESKD.…”

Epidemiology of autosomal-dominant polycystic liver disease in Olmsted county

“…Nine genes have been associated with ADPLD ( PRKCSH , SEC6 , LRP5 , GANAB , ALG8 , ALG9 , SEC61B , PKHD1 , and DNAJB11 ). [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] Together, they account for only 50–60% of the cases, suggesting that additional genes remain to be identified. Multiple hepatic cysts can also occur in association with other genetic disorders [30] , [31] , [32] and advanced chronic liver disease.…”

“… [6] , [7] , [8] , [9] The first 2 genes associated with ADPLD, PRKCSH and SEC63 , were identified in families characterised by relatively severe PLD in the absence of or with very few renal cysts. [10] , [11] , [12] Additional genes have more recently been identified to be variably associated with ADPLD, [13] , [14] , [15] , [16] , [17] , [18] , [19] but affected patients frequently exhibit renal cysts as well, pointing to a significant overlap between ADPLD and ADPKD. 20 …”

Diagnostic Utility of Exome Sequencing for Polycystic Kidney Disease

“…Additional diagnoses examined included other cystic kidney diseases (Q61.5, Q61.8, Q61.9, 753.10), acquired kidney cyst (N28.1, 593.2), congenital kidney cyst (Q61.00, Q61.01, Q61.02, 753.11, 753.19), or liver cystic disease (Q44.6, 573.8). Based on our and others’ prior studies examining ALG9 and DNAJB11(8, 23) , we anticipated that ADPKD and PLD diagnoses would be rare among carriers of atypical PTVs and therefore used a broader composite outcome of any kidney/liver cyst ICD code, which included ADPKD, cystic kidney disease, acquired renal cyst, and liver cyst diagnoses.…”

“…We assessed exome sequencing data for PTVs and CNVs among the following genes: ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT40, LRP5, PKHD, PRKCSH, SEC61B, SEC63 and examined the association of PTVs in these genes with kidney/liver cysts. Based on our and others' prior studies examining ALG9 and DNAJB11 (8,23), we anticipated that ADPKD and PLD diagnoses would be rare and therefore used a broader composite outcome of any kidney/liver cyst ICD code, which included ADPKD, cystic kidney disease, acquired renal cyst, and liver cyst diagnoses. There were 3,793 patients with rare PTVs in these 11 Overall, these data show that a genotype-first approach using high quality exome sequencing and well curated EHR to determine susceptibility to ADPKD is feasible with high positive predictive value.…”