Genetics in ADPKD

Genetics in ADPKD

Genetics in ADPKD1

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

Challenges associated with genetic testing in ADPKD 

Challenges associated with genetic testing in ADPKD 

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1250 and 200 pathogenic germline mutations in PKD1 and PKD2, respectively, have been archived at the Mayo polycystic kidney disease (PKD) database, indicating a high degree of allelic heterogeneity, with no single mutation accounting for 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 patients2,3

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

Current and evolving indications for genetic testing in ADPKD

Current and evolving indications for genetic testing in ADPKD5

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

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