Abstract
PurposeAutosomal dominant polycystic kidney disease (ADPKD) represents the most common hereditary nephropathy. Despite growing evidence for genetic heterogeneity, ADPKD diagnosis is still primarily based upon clinical imaging criteria established before discovery of additional PKD genes. This study aimed at assessing the diagnostic value of genetic verification in clinical ADPKD. MethodsIn this prospective, diagnostic trial, 100 families with clinically diagnosed ADPKD were analyzed by PKD gene panel and multiplex ligation-dependent probe amplification (MLPA); exome sequencing (ES) was performed in panel/MLPA-negative families. ResultsDiagnostic PKD1/2 variants were identified in 81 families (81%), 70 of which in PKD1 and 11 in PKD2. PKD1 variants of unknown significance were detected in another 9 families (9%). Renal survival was significantly worse upon PKD1 truncation versus nontruncation and PKD2 alteration. Ten percent of the cohort were PKD1/2-negative, revealing alternative genetic diagnoses such as autosomal recessive PKD, Birt–Hogg–Dubé syndrome, and ALG9-associated PKD. In addition, among unsolved cases, ES yielded potential novel PKD candidates. ConclusionBy illustrating vast genetic heterogeneity, this study demonstrates the value of genetic testing in a real-world PKD cohort by diagnostic verification, falsification, and disease prediction. In the era of specific treatment for fast progressive ADPKD, genetic confirmation should form the basis of personalized patient care.
Highlights
With a prevalence of 1:1000, autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary nephropathy accounting for about 10% of end-stage renal disease (ESRD).[1]
Apart from imaging, risk prediction can be improved through genetic information, as evidenced by the Predicting Renal Outcomes in ADPKD (PROPKD) score.[4]. In this single-center study, we aimed to assess the diagnostic accuracy in a cohort of clinically diagnosed ADPKD patients by means of extended genetic diagnostics based on copynumber variation analysis, targeted (PKD gene panel), and exome sequencing (ES) techniques
ADPKD diagnosis was based on medical and family history as well as on imaging data obtained by renal ultrasound, magnetic resonance imaging (MRI) and/or computed tomography according to previously defined criteria.[8,9]
Summary
With a prevalence of 1:1000, autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary nephropathy accounting for about 10% of end-stage renal disease (ESRD).[1] While ADPKD is a systemic condition, its hallmark is adult-onset bilateral cystic kidney enlargement leading to inflammation, hypertension, and progressive impairment of renal function. The main extrarenal manifestation is polycystic liver disease (PCLD) that is present in up to 94% of patients after the age of 35.2. About 10% of patients are reported to carry no pathogenic variant in PKD1/2, suggesting genetic heterogeneity.[3] More recently, pathogenic variants in a third gene, GANAB,[5] were described to result in a milder renal phenotype with predominating cystic liver disease. PKD phenocopies due to genetic variants in a number of further genes such as HNF1β, PKHD1, DNAJB11, or TSC1/2 have been reported.[6,7]
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