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The VUS Challenge in Cystic Kidney Disease: A Case-Based Review
Abinet M Aklilu1, Ashima Gulati2, Kayla J Kolber3
1Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut.
Kidney360
|November 14, 2023
Summary
Genetic testing for autosomal dominant polycystic kidney disease (ADPKD) is crucial for diagnosis and care. This study proposes an algorithm to assess variants of uncertain significance (VUSs), aiding clinicians in making genetic diagnoses.
Area of Science:
- Nephrology
- Medical Genetics
- Genomic Medicine
Background:
- Genetic testing is vital in nephrology for diagnosing conditions like autosomal dominant polycystic kidney disease (ADPKD).
- ADPKD is a common cause of kidney failure, genetically complex with multiple genes and loci involved.
- Targeted next-generation sequencing enables routine genetic testing, but variant interpretation, especially variants of uncertain significance (VUSs), presents challenges.
Purpose of the Study:
- To propose an algorithm for assessing variants of uncertain significance (VUSs) in cystic kidney genes within a clinical setting.
- To demonstrate how VUSs can be reclassified to aid in genetic diagnosis for ADPKD.
- To provide guidance for clinicians managing patients with a high clinical suspicion of ADPKD but no identified pathogenic variants.
Main Methods:
- Review of case studies involving patients with suspected ADPKD and variants of uncertain significance (VUSs).
- Development of a systematic algorithm for VUS assessment, incorporating patient/family-specific and allele-related factors.
- Utilizing population and variant databases, prediction tools, and expert genetic review.
Main Results:
- The proposed algorithm facilitates the reassessment and potential reclassification of VUSs in cystic kidney genes.
- Integration of clinical data, population databases, prediction tools, and genetic expertise aids in variant interpretation.
- Successful reclassification of some VUSs can lead to a definitive genetic diagnosis for ADPKD.
Conclusions:
- A structured approach to evaluating VUSs is essential for accurate genetic diagnosis in ADPKD.
- The proposed algorithm assists clinicians in navigating the complexities of genetic variant interpretation.
- Further family studies and robust variant databases are crucial for advancing genetic diagnostics in nephrology.
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