Abstract: TH-PO452
Reclassification of Genetic Diagnoses: Need for Structure in Re-Evaluation of Genetic Findings
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania 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
- Schott, Clara, Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
- Baker, Cadence, London Health Sciences Centre, London, Ontario, Canada
- Colaiacovo, Samantha, London Health Sciences Centre, London, Ontario, Canada
- Connaughton, Dervla M., Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
Introduction
Constant advances and emerging data in genomic medicine causes classification of genetic findings to be dynamic. In kidney disease (KD) alone, the number of single gene disorders are increasing, with over 600 genes described thus far. Genetic variant pathogenicity is classified according to the American College of Medical Genetics (ACMG) guidelines. Although the ACMG guidelines provide a classification with >95% certainty, variants of unknown significance (VUS), which do not have enough information to classify, may be reclassified when more information becomes available. The ACMG guidelines suggest that all new data should be incorporated into the genetic evaluation as it becomes available. This includes, but is not limited to, any new patient specific clinical information, family data, and population and case data in the literature. Currently, there are no protocols guiding when and how often to reevaluate genomic data. We present a case which highlights the importance of periodic genetic re-evaluation in a living donor post kidney donation.
Case Description
A 45-year-old female donated her left kidney as a non-directed altruistic donor. At the time of donor assessment, her creatinine was normal (60-70mmol/L), however, she had persistent microscopic hematuria. Given a positive family history of KD in a maternal uncle, genetic testing was performed. This revealed a variant of unknown significance (VUS) in COL4A4 c.3307G>A, p.G1103R. Since a VUS is not considered a clinically actionable finding, she elected to proceed with donation. Unfortunately, 5-years post-donation, she had progressive rise in creatinine (125 umol/L). An updated pedigree analysis now revealed that two of her children had developed KD and hearing impairment, prompting reanalysis. New clinical data and additional data in literature supported pathogenicity of this variant warranting reclassification to pathogenic, supporting a familial diagnosis of Alport Syndrome.
Discussion
We show that reevaluation of patient genomics can lead to reclassification of previously identified variants, which can have significant clinical implications for the patient and at-risk family members. This case highlights both the importance of re-analysis of genomic data and the clinical implications of establishing a genetic diagnosis for family screening and decision making for transplants.