Abstract: FR-PO645
Challenges and Results of ClinGen Gene-Disease Clinical Validity Curation for Complement-Mediated Kidney Disease
Session Information
- Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Wongboonsin, Janewit, Brigham and Women's Hospital, Boston, United States
- Webb, Ryan Fraser, Broad Institute, Cambridge, Massachusetts, United States
- Robertson, Pamela A., Broad Institute, Cambridge, Massachusetts, United States
- Byrne, Alicia B., Broad Institute, Cambridge, Massachusetts, United States
- Caliskan, Yasar, Saint Louis University, St Louis, Missouri, United States
- Java, Anuja, Washington University in St Louis, St Louis, Missouri, United States
- Kavanagh, David, National Renal Complement Therapeutics Center, Newcastle, United Kingdom
Group or Team Name
- ClinGen Complement-Mediated Kidney Diseases Gene Curation Expert Panel.
Background
ClinGen is a National Institutes of Health-funded central resource to systematically evaluate the clinical validity of gene-disease relationships (GDRs) and assess variant pathogenicity. The ClinGen Kidney Disease Clinical Domain Working Group (CDWG) was established in 2019 to focus on monogenic kidney diseases. In 2022, the Complement-Mediated Kidney Disease Gene Curation Expert Panel (CMKD-GCEP) began its work by focusing on atypical hemolytic uremic syndrome (aHUS), and C3 glomerulopathy (C3G). GDR evaluation is crucial for clinical testing as it provides the foundational evidence necessary for variant interpretation
Methods
ClinGen's evidence-based semi-quantitative gene curation framework has been implemented across GCEPs. This framework encompasses genetic and experimental evidence. Genetic evidence includes case-level data, family segregation, and case-control data, while experimental evidence comprises data from functional assays and related models. The final clinical validity of the GDR is categorized into levels ranging from Refuted to Definitive. Curations undergo review by the GCEP, with feedback from complementologists incorporated to refine curation practices
Results
To date, CMKD-GCEP has evaluated 7 genes associated with aHUS and C3G. Well-known genes such as C3, CFH, CFI, and CFB were prioritized for curation and achieved Definitive GDR classifications for aHUS. THBD was refuted. We encountered a challenge in curating CFH-related proteins as the framework was tailored for small nucleotide variants (SNVs). CFHR1 was the first gene curated with a limited number of SNV cases, resulting in insufficient evidence. Given the number of cases with structural variants (SV), the GCEP modified the framework to incorporate genetic evidence from SVs, thereby elevating the strength from Limited to Moderate. As only genes with at least Moderate evidence can be considered for clinical genetic testing, neglecting SVs would weaken evidence strength, hindering further genomic discoveries in complementopathy.
Conclusion
The CMKD-GCEP was established to offer high-quality GDR evidence to the public. With combined input from renal complementologists and ClinGen framework experts, the curation framework can be adapted to accommodate challenging kidney-affecting genes, such as CFHR1