Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease

Hopp, Katharina; Gall, Emilie Cornec-Le; Senum, Sarah R.; Paske, Iris B A W Te; Raj, Sonam; Lavu, Sravanthi; Baheti, Saurabh; Edwards, Marie E.; Madsen, Charles D.; Heyer, Christina M.; Ong, Albert; Bae, Kyongtae T.; Fatica, Richard; Steinman, Theodore I.; Chapman, Arlene B.; Gitomer, Berenice; Perrone, Ronald D.; Rahbari-Oskoui, Frederic F.; Torres, Vicente E.; Harris, Peter C.

doi:10.1016/j.kint.2019.08.038

Cited by 51 publications

(59 citation statements)

References 35 publications

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“…The entire coding and flanking intronic regions of PKD1 and PKD2 were screened for mutations by Sanger or next generation sequencing as previously described. 19 , 20 , 21 , 22 Patients were classified as follows: PKD1 truncating ( PKD1 T ), PKD1 nontruncating ( PKD1 NT ), and PKD2 . PKD1 NT mutations were subcategorized to PKD1 NT1 and PKD1 NT2 .…”

Section: Methodsmentioning

confidence: 99%

Characteristics of Patients with End-Stage Kidney Disease in ADPKD

Shukoor

Vaughan

Edwards

et al. 2021

Kidney International Reports

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Introduction Cystic expansion damaging the parenchyma is thought to lead to end-stage kidney disease (ESKD) in autosomal dominant polycystic kidney disease (ADPKD). Here we characterized genotypic and phenotypic attributes of ADPKD at time of ESKD. Methods This is a retrospective cross-sectional study of patients with ADPKD with ESKD evaluated at Mayo Clinic with available abdominal computed tomography (CT) or magnetic resonance imaging (MRI). Kidney volumes were measured (total kidney volume adjusted for height [HtTKV]), Mayo Image Class (MIC) calculated, ADPKD genotype determined, and clinical and laboratory features obtained from medical records. Results Differences in HtTKV at ESKD were associated with patient age and sex; older patients and women had smaller HtTKV at ESKD. HtTKV at ESKD was observed to be 12.3% smaller with each decade of age ( P < 0.01); but significant only in women (17.8%, P < 0.01; men 6.9%, P = 0.06). Patients with onset of ESKD at <47, 47–61, or >61 years had different characteristics, with a shift from youngest to oldest in male to female enrichment, MIC from 1D/1E to 1B/1C, likely fully penetrant PKD1 mutations from 95% to 42%, and presence of macrovascular disease from 8% to 40%. Macrovascular disease was associated with smaller kidneys in female patients. Conclusion HtTKV at ESKD was smaller with advancing age in patients with ADPKD, particularly in women. These novel findings provide insight into possible underlying mechanisms leading to ESKD, which differ between younger and older individuals. Cystic growth is the predominant mechanism in younger patients with ESKD, whereas aging-related factors, including vascular disease, becomes potentially important as patients age.

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Section: Methodsmentioning

confidence: 99%

Characteristics of Patients with End-Stage Kidney Disease in ADPKD

Shukoor

Vaughan

Edwards

et al. 2021

Kidney International Reports

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“…Details about the TNGS panel employed in Mayo have been published recently. 33 All changes were confirmed by Sanger sequencing. When family samples were available, segregation analysis of the variant of interest was performed.…”

Section: Molecular Analysesmentioning

confidence: 99%

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

Huynh¹,

Audrézet²,

Sayer³

et al. 2020

Kidney International

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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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“…Mutation screening was performed by Sanger sequencing or employing a next-generation sequencing panel (11,43,44). Patients with PKD1 mutations were categorized into truncating (PKD1 T ; inactivating; previously termed MSG1) or nontruncating changes predicted to be fully penetrant (PKD1 NT1 ; MSG2) or hypomorphic (PKD1 NT2 ; MSG3).…”

Section: Genetic Characterizationmentioning

confidence: 99%

“…Patients with a clinical ADPKD phenotype seen at Mayo Clinic, genetically defined as PKD1 or PKD2 and with a typical MIC, were considered for the Analysis Cohort (N = 1328; Figure 1). Subjects with complex genotypes or missing clinical data within the timescale of the study were excluded, leaving 1079 for the renal survival analysis (Figure 1) (33,44). Other exclusions were implemented depending on the measured outcome ( Figure 1).…”

Section: Study Populationsmentioning

confidence: 99%

The value of genotypic and imaging information to predict functional and structural outcomes in ADPKD

Lavu

Vaughan²,

Senum

et al. 2020

JCI Insight

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BACKGROUND. A treatment option for autosomal dominant polycystic kidney disease (ADPKD) has highlighted the need to identify rapidly progressive patients. Kidney size/age and genotype have predictive power for renal outcomes, but their relative and additive value, plus associated trajectories of disease progression, are not well defined. METHODS. The value of genotypic and/or kidney imaging data (Mayo Imaging Class; MIC) to predict the time to functional (end-stage kidney disease [ESKD] or decline in estimated glomerular filtration rate [eGFR]) or structural (increase in height-adjusted total kidney volume [htTKV]) outcomes were evaluated in a Mayo Clinic PKD1/PKD2 population, and eGFR and htTKV trajectories from 20-65 years of age were modeled and independently validated in similarly defined CRISP and HALT PKD patients. RESULTS. Both genotypic and imaging groups strongly predicted ESKD and eGFR endpoints, with genotype improving the imaging predictions and vice versa; a multivariate model had strong discriminatory power (C-index = 0.845). However, imaging but not genotypic groups predicted htTKV growth, although more severe genotypic and imaging groups had larger kidneys at a young age. The trajectory of eGFR decline was linear from baseline in the most severe genotypic and imaging groups, but it was curvilinear in milder groups. Imaging class trajectories differentiated htTKV growth rates; severe classes had rapid early growth and large kidneys, but growth later slowed. CONCLUSION. The value of imaging, genotypic, and combined data to identify rapidly progressive patients was demonstrated, and reference values for clinical trials were provided. Our data indicate that differences in kidney growth rates before adulthood significantly define patients with severe disease.

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Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease

Cited by 51 publications

References 35 publications

Characteristics of Patients with End-Stage Kidney Disease in ADPKD

Characteristics of Patients with End-Stage Kidney Disease in ADPKD

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

The value of genotypic and imaging information to predict functional and structural outcomes in ADPKD

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