Framework for prioritizing variants of unknown significance from clinical genetic testing in kidney disease: utility of multidisciplinary approach to gather evidence of pathogenicity for Hepatocyte Nuclear Factor-1 (HNF1B) p.Arg303His

Abstract

Monogenic causes in over 300 kidney-associated genes account for roughly 12% of end stage kidney disease (ESKD) cases. Advances in next generation sequencing, and large customized panels enable the diagnosis of monogenic kidney disease noninvasively at relatively low cost, allowing for more precise management for patients and their families. A major challenge is interpreting rare variants, many of which are classified as variants of unknown significance (VUS). We present a framework in which we thoroughly evaluated and provided evidence of pathogenicity for HNF1B-p.Arg303His, a VUS returned from clinical genetic testing for a kidney transplant candidate. This blueprint, designed by a multi-disciplinary team of clinicians, molecular biologists, and diagnostic geneticists, includes using a health system-based cohort with genetic and clinical information to perform deep phenotyping of VUS carriers, examination of existing genetic databases, as well as functional testing. With our approach, we demonstrate evidence for pathogenicity for HNF1B-p.Arg303His by showing similar burden of kidney manifestations in this variant to known HNF1B pathogenic variants, and greater burden compared to non-carriers. Determination of a molecular diagnosis for the example family allows for proper surveillance and management of HNF1B-related manifestations such as kidney disease, diabetes, and hypomagnesemia with important implications for safe living-related kidney donation. The candidate gene-variant pair also allows for clinical biomarker testing for aberrations of linked pathways. This working model may be applicable other diseases of genetic etiology.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was financially supported by a grant from the Dutch Kidney Foundation to J. de Baaij (Large Kolff grant 17OKG07) and J. Hoenderop (IMAGEN project which is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, LSHM20009).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of Geisinger Medical Center gave ethical approval for this work.

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Data Availability

All data produced in the present study are available upon reasonable request to the authors.

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