Abstract: SA-PO606
Genetic and Clinical Characterization of Patients with ADPKD and Intracranial Aneurysms: The PKD-VASC Cohort
Session Information
- Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
October 26, 2024 | 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: Cystic
Authors
- Patel, Puja, University of Maryland Baltimore, Baltimore, Maryland, United States
- Besse, Whitney, Yale University School of Medicine, New Haven, Connecticut, United States
- Gulati, Ashima, Children's National Research & Innovation Campus, Washington, District of Columbia, United States
- Shaw, Melissa M., Yale University School of Medicine, New Haven, Connecticut, United States
- Blumenfeld, Jon D., Rogosin Institute, New York, New York, United States
- Pei, York, University Health Network, Toronto, Ontario, Canada
- Gitomer, Berenice Y., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Perrone, Ronald D., Tufts Medical Center, Boston, Massachusetts, United States
- Caliskan, Yasar, Saint Louis University School of Medicine, St Louis, Missouri, United States
- Park, Hayne C., Hallym University Kangnam Sacred Heart Hospital, Yeongdeungpo-gu, Seoul, Korea (the Republic of)
- Yu, Alan S.L., The University of Kansas Medical Center, Kansas City, Kansas, United States
- Dahl, Neera K., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Rahbari-Oskoui, Frederic F., Emory University School of Medicine, Atlanta, Georgia, United States
- Somlo, Stefan, Yale University School of Medicine, New Haven, Connecticut, United States
- Watnick, Terry J., University of Maryland Baltimore, Baltimore, Maryland, United States
Background
ADPKD is associated with a ~4-5-fold increase in the prevalence of intracranial aneurysm (ICA) compared with the general population. This risk is intensified ~4-fold in ADPKD families with a history of ICA suggesting an inherited predisposition.
Methods
To investigate the genetic underpinnings of ICA in ADPKD, we assembled an international cohort of individuals with ADPKD and ICA: the PKD-Vasc cohort. We collected clinical data and DNA for whole exome sequencing (WES) from 289 self-referred participants or colleague-referred de-identified cases with both ADPKD and ICA.
Results
The PKD-Vasc cohort is ~70% female and 46% had either a ruptured ICA or required neurosurgical intervention. The remaining 54% had an unruptured ICA of at least 2mm and 22.5% had more than one ICA. Most participants (85%) had a family history of ADPKD and 38% had a family history of ADPKD with ICA. Of note 19% had a history of ICA in a family member without a diagnosis of ADPKD. Most participants (89%) were hypertensive, most had never smoked cigarettes, and a minority (18%) had ESKD at the time of their ICA diagnosis. As has been reported, most unruptured ICA were small (<5mm) and located in the middle cerebral, internal carotid, and anterior communicating arteries. WES identified a PKD1 mutation in 220/289 (76%), a PKD2 mutation in 38/289 (13%) and there was no causative mutation detected in 11%. A small number of cases had disease caused by minor ADPKD genes. These cases were excluded from primary analysis. Among participants with truncating PKD1 variants, 55% had a ruptured ICA or an ICA requiring intervention. We looked at the distribution of truncating and non-truncating PKD1 mutations and we found that variants were scattered along the gene with no obvious genotype/phenotype correlation.
Conclusion
Genetic modifiers in the setting of PKD1/PKD2 may influence the risk of ICA. The PKD-Vasc cohort will be a valuable tool for investigating this question.
Distribution of PKD1 mutations plotted against their amino acid location within the PKD1 protein.
Funding
- Other U.S. Government Support