Abstract: SA-PO0593
Investigating the Role of the Mitochondrial Genome in Phenotypes of PKD
Session Information
- Cystic Kidney Diseases: Clinical Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Heneghan, Sophia, Royal College of Surgeons in Ireland, Dublin, Leinster, Ireland
- Elhassan, Elhussein Aamir Elzein, Beaumont Hospital, Dublin, Ireland
- Teltsh, Omri, Royal College of Surgeons in Ireland, Dublin, Leinster, Ireland
- Gilbert, Edmund H., Royal College of Surgeons in Ireland, Dublin, Leinster, Ireland
- Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
- Cavalleri, Gianpiero, Royal College of Surgeons in Ireland, Dublin, Leinster, Ireland
Group or Team Name
- Human Genetics Research Group.
Background
Cystic cells in polycystic kidney disease (PKD) adopt a tumor-like metabolic state, though the mechanism remains unclear. Mitochondrial DNA (mtDNA) variants, including heteroplasmic variants and those that define haplogroups, have been associated with kidney phenotypes. Mitochondrial abnormalities identified in PKD cysts suggest a potential role in disease progression. Here, we present the investigation of mitochondrial variants in a PKD cohort.
Methods
Exome sequencing with a mtDNA spike-in was available for 303 PKD patients from the Irish Kidney Gene Project. 281 samples with >80x mtDNA coverage were kept for analysis. GATK Mutect2 (mitochondrial mode) was used to call mtDNA variants; variants in homopolymeric tracts were excluded. Variants were annotated using MSeqDr, VEP, and MitImpact. Haplogrep3 was used to assign haplogroups using variants with variant allele frequency >0.95. To identify pathogenic variants, nuclear-encoded mitochondrial genes (NEMGs, n=236) were filtered for nonsynonymous variants with allele frequency <0.005 and mtDNA variants with allele frequency <0.001. Ancestry principal components were calculated by projecting PKD individuals with SNP array (n=266) onto Irish-like reference individuals (n=2604). A Cox proportional hazards model in R was used to test for associations between mtDNA haplogroups and kidney survival, correcting for sex, diagnostic variant, and ancestry.
Results
638 mtDNA variants passed QC filtering, with 84 found as heteroplasmic (heteroplasmy range: 20%-95%). ACMG classification indicates no pathogenic mtDNA variants, and classification is underway for NEMG variants. Haplogroups were assigned to 276 individuals, with 10 distinct haplogroups occurring in the cohort. Regression analyses suggested that haplogroup U is associated with increased kidney survival (Bonferroni adjusted-p=0.003) compared to other haplogroups. However, testing in additional cohorts is required to validate this signal.
Conclusion
Mitochondrial variation even within a small Irish PKD cohort is quite diverse. No heteroplasmic variants causing PKD were identified in this cohort. Regression analyses suggested that haplogroup U may have a protective effect in kidney survival in PKD, but this signal must be replicated in another cohort.
Funding
- Commercial Support – BioMarin Pharmaceutical