Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic...

Area of Science:

• Genetics
• Nephrology
• Molecular Biology

Background:

• Monogenic causes in over 300 kidney-associated genes account for approximately 12% of end-stage kidney disease (ESKD) cases.
• Advances in genetic sequencing enable noninvasive diagnosis of monogenic kidney disease, but interpreting variants of unknown significance (VUS) remains a challenge.
• Accurate variant interpretation is essential for precise patient management and family counseling.

Purpose of the Study:

• To develop and present a framework for evaluating and establishing the pathogenicity of VUS in kidney-associated genes.
• To provide evidence of pathogenicity for the HNF1B-p.Arg303His variant, identified in a kidney transplant candidate.

Main Methods:

• A multidisciplinary team designed a blueprint involving deep phenotyping of VUS heterozygotes within a health system-based cohort.
• Methods included examining existing genetic databases and performing functional testing.
• Comparison of kidney manifestation burden between VUS carriers, non-carriers, and individuals with known pathogenic variants.

Main Results:

• The study demonstrated evidence of pathogenicity for HNF1B-p.Arg303His.
• Individuals with this variant showed a similar burden of kidney manifestations compared to known HNF1B pathogenic variants.
• A greater burden of kidney manifestations was observed in carriers compared to non-carriers.

Conclusions:

• Establishing a molecular diagnosis for HNF1B-p.Arg303His enables proper surveillance and management of associated conditions like kidney disease, diabetes, and hypomagnesemia.
• This has significant implications for living-related kidney donation and allows for clinical biomarker testing.
• The developed framework may be applicable to other genetic diseases.