The Value of Genetic Testing in Polycystic Kidney Diseases Illustrated by a Family With PKD2 and COL4A1 Mutations

Am J Kidney Dis. 2018 Aug;72(2):302-308. doi: 10.1053/j.ajkd.2017.11.015. Epub 2018 Feb 1.


The diagnosis of autosomal dominant polycystic kidney disease (ADPKD) relies on imaging criteria in the setting of a positive familial history. Molecular analysis, seldom used in clinical practice, identifies a causative mutation in >90% of cases in the genes PKD1, PKD2, or rarely GANAB. We report the clinical and genetic dissection of a 7-generation pedigree, resulting in the diagnosis of 2 different cystic disorders. Using targeted next-generation sequencing of 65 candidate genes in a patient with an ADPKD-like phenotype who lacked the familial PKD2 mutation, we identified a COL4A1 mutation (p.Gln247*) and made the diagnosis of HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome. While 4 individuals had ADPKD-PKD2, various COL4A1-related phenotypes were identified in 5 patients, and 3 individuals with likely digenic PKD2/COL4A1 disease reached end-stage renal disease at around 50 years of age, significantly earlier than observed for either monogenic disorder. Thus, using targeted next-generation sequencing as part of the diagnostic approach in patients with cystic diseases provides differential diagnoses and identifies factors underlying disease variability. As specific therapies are rapidly developing for ADPKD, a precise etiologic diagnosis should be paramount for inclusion in therapeutic trials and optimal patient management.

Keywords: Autosomal dominant polycystic kidney disease (ADPKD); COL4A1; HANAC; PKD2; case report; genetic testing; pedigree; phenotypic variability; targeted next-generation sequencing (TNGS).

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Collagen Type IV / genetics*
  • Genetic Testing / methods*
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Polycystic Kidney Diseases / diagnostic imaging*
  • Polycystic Kidney Diseases / genetics*
  • TRPP Cation Channels / genetics*


  • COL4A1 protein, human
  • Collagen Type IV
  • TRPP Cation Channels
  • polycystic kidney disease 2 protein