Genetics in ADPKD

Average age at onset of kidney failure is associated with:

• PKD1 truncating - most severe (56 YO)
• PKD1 non-truncating – intermediate (68 YO)
• PKD2 mutation - least severe (79 YO)
• family history of member with Kidney failure < 55 YO = PKD1 mutation prediction
• family history of member with Kidney failure > 70 YO = PKD2 mutation prediction¹

Analysis of PKD1 is technically challenging due to its large size, high guanine–cytosine (GC) content and duplication of the first 33 exons with a high degree of homology  (>98% identity) to six nearby pseudogenes (PKD1P1–P6)²

To date, >1250 and 200 pathogenic germline mutations in PKD1 and PKD2, respectively, have been archived at the Mayo polycystic kidney disease (PKD) database, indicating a high degree of allelic heterogeneity, with no single mutation accounting for >2% of patients^2,3

Additionally, pathogenic mutations are found throughout the length of both genes with no obvious clustering or "hot spots"⁴

Scenarios where genetic testing is clinically indicated:

• Suspected ADPKD with no apparent family history
• Suspected ADPKD with equivocal renal imaging findings
• ADPKD exclusion in young (e.g. <25 years old) at-risk subjects

  • Living-related kidney donation evaluation
  • Obtaining life or disability insurance
• Prenatal and preimplantation genetic diagnosis
• Scenarios with evolving indication for genetic testing

  • Identifying ‘high-risk’ patients for novel disease modifier therapy or clinical trial
• Delineating the cause of atypical clinical presentation

  • Early and severe disease
  • Discrepancy between imaging findings and decrease in renal function
  • Asymmetric, unilateral, segmental or lopsided cystic kidneys
  • Marked intrafamilial disease discordance
  • Suspected somatic mosaicism
  • Syndromic forms of polycystic kidney disease