Kidney Week

Abstract: FR-PO656

Genotype-Phenotype Correlations in Combined Kidney Histopathology and Genetic Testing on a 385-Gene Kidney Disease Panel

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

• Riella, Cristian, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Cristian Riella, MD

• Colombo, Dan, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Dan Colombo

• Rennke, Helmut G., Brigham and Women's Hospital, Boston, Massachusetts, United States

Helmut G. Rennke, MD

• Stillman, Isaac Ely, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Isaac Ely Stillman, MD

• Weins, Astrid, Brigham and Women's Hospital, Boston, Massachusetts, United States

Astrid Weins, MD, PhD, FASN

• Rosen, Seymour, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Seymour Rosen, MD

• Heher, Yael K., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Yael K. Heher, MD, MPH

• Bianchi, Giada, Brigham and Women's Hospital, Boston, Massachusetts, United States

Giada Bianchi, MD

• Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States

Anthony J. Bleyer, MD, MS, FASN

• Kmoch, Stanislav, Univerzita Karlova, Praha, Czechia

Stanislav Kmoch

• Lu, Weining, Boston University, Boston, Massachusetts, United States

Weining Lu, MD, MS, FASN

• Czarnecki, Peter G., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Peter G. Czarnecki, MD

Background

The magnitude of causative and contributory genetic mechanisms in adult chronic kidney disease is unknown. We aimed to investigate genotype data from large kidney disease gene panel tests in the context of histopathologic findings and identify the diagnostic strengths of both methods alone and in combination. We further sought to find correlations between genetic variants and histologic and ultrastructural phenotypes.

Methods

We analyzed genetic test results, clinical parameters of kidney disease and renal histopathology findings in 115 patients from two major academic medical centers in Boston.

Results

In 37.4% of cases, kidney disease was sufficiently diagnosed by pathology, in 34.8% of cases a precision diagnosis was made by combined pathology and genetic testing, and in 33.0% of cases, pathology only delivered a less specific pattern diagnosis. Genetic testing alone led to a final diagnosis in 29.6% of cases, and it was particularly powerful in cohorts with positive family history of CKD and in the absence of diabetes, glomerulonephritis or immune deposition disease. We discovered a surprisingly high amount of TBMN-Alport-spectrum disease with no detectable collagen gene mutations (63.3%). We also demonstrate that the magnitude of age-independent global glomerulosclerosis strongly correlates with the presence of genetic variants in ADTKD-, CAKUT- and podocyte genes. In the course of our analysis, we identified variants of uncertain significance in at least 10 kidney disease genes that are potentially pathogenic.

Conclusion

Our study highlights the specific strengths of combined histopathology and genetic testing in the precision diagnosis of renal parenchymal disease, suggesting genetic causation in patients with positive family histories, absence of diabetes, glomerulonephritis and immune deposition disease. We demonstrate the genetic complexity of TBMN-Alport-spectrum disease that is far beyond collagen-IVα mutation, and we find supporting evidence for the hypothesis that age-independent global glomerulosclerosis is driven by genetic factors.

Funding

• NIDDK Support