Polycystic Kidney Disease Inheritance
Autosomal dominant polycystic kidney disease (ADPKD) is inherited in an autosomal dominant pattern, meaning each child of an affected parent has a 50% chance of inheriting the disease-causing mutation. 1
Inheritance Pattern
- ADPKD follows autosomal dominant inheritance, where a single pathogenic variant in one copy of a disease-causing gene is sufficient to cause the condition 1
- Each offspring of an affected individual has a 50% probability of inheriting the mutation, regardless of sex 1
- Both males and females are equally affected, as the genes are located on autosomes (non-sex chromosomes) 1
Genetic Complexity
Major Genes
- PKD1 and PKD2 account for >90% of diagnosed ADPKD families 1
- PKD1 mutations represent approximately 48% of screened families with truncating variants and 19% with nontruncating variants 1
- PKD2 mutations account for approximately 15% of families 1
- PKD1 mutations cause more severe disease, with kidney failure typically occurring in the 50s, compared to PKD2 mutations where kidney failure occurs in the 70s 1
Minor Genes
- Several minor genes account for <0.5% each of ADPKD families, including IFT140, ALG5, ALG9, GANAB, DNAJB11, and NEK8 1
- These minor genes generally cause milder kidney disease, though DNAJB11 and ALG5 have kidney failure timing similar to PKD2 1, 2
Special Genetic Scenarios
De Novo Mutations
- Up to 10% of ADPKD cases occur without a family history due to de novo (new) mutations 1
- NEK8 mutations show de novo occurrence in 75% of cases 1
Mosaicism
- Somatic mosaicism can occur, where the mutation arises early in embryonic development, leading to variable disease severity 1, 2
- Mosaicism is sometimes associated with PKD1 truncating variants and can result in a more benign course 1
Biallelic Disease
- Rarely, individuals inherit pathogenic variants from both parents (biallelic disease), causing very early-onset ADPKD with severe manifestations 2
- This represents additional genetic complexity beyond typical autosomal dominant inheritance 2
Genetic Counseling Implications
Family Screening
- Genetic testing is particularly valuable for young living-related kidney donors at risk based on family history 1, 3, 4
- Testing helps with family planning and preimplantation genetic diagnosis decisions 1, 3, 4
- In genetically resolved families, simple testing of the known family variant usually provides diagnosis 1, 3
Prognostic Information
- The specific gene involved (PKD1 vs PKD2 vs minor genes) significantly impacts disease severity and timing of kidney failure 1, 2
- Type of PKD1 mutation (truncating vs nontruncating) affects prognosis, with truncating variants generally causing more severe disease 1
- Sex and environmental factors (obesity, salt intake) also influence disease severity 1, 4
Autosomal Recessive Polycystic Kidney Disease (ARPKD)
- ARPKD follows autosomal recessive inheritance, requiring pathogenic variants in both copies of the gene 2, 5
- Both parents must be carriers (heterozygotes) for a child to be affected, with a 25% recurrence risk for each pregnancy 2
- PKHD1 is the major gene causing ARPKD, with DZIP1L and CYS1 as minor genes 2
- ARPKD typically presents in infancy with severe disease, contrasting with the adult-onset of ADPKD 2, 5
Clinical Pitfall
Do not assume negative family history excludes ADPKD—approximately 10% of cases arise from de novo mutations, and variable expressivity means some family members may have mild, undiagnosed disease 1, 2