Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification

Uyenlinh L. Mirshahi; Ahana Bhan; Lotte E. Tholen; Brian Fang; Guoli Chen; Bryn Moore; Adam Cook; Prince Mohan Anand; Kashyap Patel; Mary E. Haas; Luca A. Lotta; Peter Igarashi; Jeroen H.F. de Baaij; Silvia Ferrè; Joost G.J. Hoenderop; David J. Carey; Alexander R. Chang

doi:10.1016/j.ekir.2022.06.014

Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification

Uyenlinh L. Mirshahi, Ahana Bhan, Lotte E. Tholen, Brian Fang, Guoli Chen, Bryn Moore, Adam Cook, Prince Mohan Anand, Kashyap Patel, Mary E. Haas, Luca A. Lotta, Peter Igarashi, Jeroen H.F. de Baaij, Silvia Ferrè, Joost G.J. Hoenderop, David J. Carey, Alexander R. Chang

Medicine - Renal and Hypertension Division

Research output: Contribution to journal › Article › peer-review

Abstract

Introduction: Monogenic causes in over 300 kidney-associated genes account for approximately 12% of end stage kidney disease (ESKD) cases. Advances in sequencing and large customized panels enable the noninvasive diagnosis of monogenic kidney disease at relatively low cost, thereby 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 diagnostic testing for a kidney transplant candidate. Methods: A blueprint was designed by a multidisciplinary team of clinicians, molecular biologists, and diagnostic geneticists. The blueprint included using a health system-based cohort with genetic and clinical information to perform deep phenotyping of VUS heterozygotes to identify the candidate VUS and rule out other VUS, examination of existing genetic databases, as well as functional testing. Results: Our approach demonstrated 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 noncarriers. Conclusion: 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 to other diseases of genetic etiology.

Original language	English (US)
Pages (from-to)	2047-2058
Number of pages	12
Journal	Kidney International Reports
Volume	7
Issue number	9
DOIs	https://doi.org/10.1016/j.ekir.2022.06.014
State	Published - Sep 2022

Bibliographical note

Funding Information:
The authors would like to acknowledge the participants of the MyCode Community Health Initiative for use of their genomic and electronic health information, without whom this study would not be possible. The patient enrollment and exome sequencing were funded by the Regeneron Genetics Center. We thank the Geisinger-Regeneron DiscovEHR Collaboration for making the genotype data and phenotype available for this project. We are grateful to the laboratory of Dr. Tooraj Mirshahi for the use of the genetic database. We thank Dr. Matthew Oetjens for helpful discussions on the confirmation of exome copy number variations calls using genotyping array. We thank Dr. Natasha Strande for critical comments on the manuscript. We thank the ClinGen Monogenic Diabetes Variation Curation Expert Panel for helpful discussions regarding this variant.

Funding Information:
This work was financially supported by a grant from the Dutch Kidney Foundation to JHF de B (Large Kolff grant 17OKG07) and JGJH (IMAGEN project which is cofunded by the PPP Allowance made available by Health∼Holland, Top Sector Life Sciences & Health, LSHM20009). KAP has a Career Development fellowship funded by the Wellcome Trust (219606/Z/19/Z). For the purpose of open access, the authors have applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. PI is supported by an NIH grant R01DK042921.

Funding Information:
The authors would like to acknowledge the participants of the MyCode Community Health Initiative for use of their genomic and electronic health information, without whom this study would not be possible. The patient enrollment and exome sequencing were funded by the Regeneron Genetics Center. We thank the Geisinger-Regeneron DiscovEHR Collaboration for making the genotype data and phenotype available for this project. We are grateful to the laboratory of Dr. Tooraj Mirshahi for the use of the genetic database. We thank Dr. Matthew Oetjens for helpful discussions on the confirmation of exome copy number variations calls using genotyping array. We thank Dr. Natasha Strande for critical comments on the manuscript. We thank the ClinGen Monogenic Diabetes Variation Curation Expert Panel for helpful discussions regarding this variant.

Publisher Copyright:
© 2022 International Society of Nephrology

Keywords

HNF1B-MODY
autosomal dominant tubulointerstitial kidney disease (ADTKD)
chronic kidney disease
genetics
hypomagnesemia
pancreatitis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ekir.2022.06.014

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Mirshahi, U. L., Bhan, A., Tholen, L. E., Fang, B., Chen, G., Moore, B., Cook, A., Anand, P. M., Patel, K., Haas, M. E., Lotta, L. A., Igarashi, P., de Baaij, J. H. F., Ferrè, S., Hoenderop, J. G. J., Carey, D. J., & Chang, A. R. (2022). Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification. Kidney International Reports, 7(9), 2047-2058. https://doi.org/10.1016/j.ekir.2022.06.014

Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification. / Mirshahi, Uyenlinh L.; Bhan, Ahana; Tholen, Lotte E. et al.
In: Kidney International Reports, Vol. 7, No. 9, 09.2022, p. 2047-2058.

Research output: Contribution to journal › Article › peer-review

Mirshahi, UL, Bhan, A, Tholen, LE, Fang, B, Chen, G, Moore, B, Cook, A, Anand, PM, Patel, K, Haas, ME, Lotta, LA, Igarashi, P, de Baaij, JHF, Ferrè, S, Hoenderop, JGJ, Carey, DJ & Chang, AR 2022, 'Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification', Kidney International Reports, vol. 7, no. 9, pp. 2047-2058. https://doi.org/10.1016/j.ekir.2022.06.014

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title = "Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification",

abstract = "Introduction: Monogenic causes in over 300 kidney-associated genes account for approximately 12% of end stage kidney disease (ESKD) cases. Advances in sequencing and large customized panels enable the noninvasive diagnosis of monogenic kidney disease at relatively low cost, thereby 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 diagnostic testing for a kidney transplant candidate. Methods: A blueprint was designed by a multidisciplinary team of clinicians, molecular biologists, and diagnostic geneticists. The blueprint included using a health system-based cohort with genetic and clinical information to perform deep phenotyping of VUS heterozygotes to identify the candidate VUS and rule out other VUS, examination of existing genetic databases, as well as functional testing. Results: Our approach demonstrated 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 noncarriers. Conclusion: 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 to other diseases of genetic etiology.",

keywords = "HNF1B-MODY, autosomal dominant tubulointerstitial kidney disease (ADTKD), chronic kidney disease, genetics, hypomagnesemia, pancreatitis",

author = "Mirshahi, {Uyenlinh L.} and Ahana Bhan and Tholen, {Lotte E.} and Brian Fang and Guoli Chen and Bryn Moore and Adam Cook and Anand, {Prince Mohan} and Kashyap Patel and Haas, {Mary E.} and Lotta, {Luca A.} and Peter Igarashi and {de Baaij}, {Jeroen H.F.} and Silvia Ferr{\`e} and Hoenderop, {Joost G.J.} and Carey, {David J.} and Chang, {Alexander R.}",

note = "Funding Information: The authors would like to acknowledge the participants of the MyCode Community Health Initiative for use of their genomic and electronic health information, without whom this study would not be possible. The patient enrollment and exome sequencing were funded by the Regeneron Genetics Center. We thank the Geisinger-Regeneron DiscovEHR Collaboration for making the genotype data and phenotype available for this project. We are grateful to the laboratory of Dr. Tooraj Mirshahi for the use of the genetic database. We thank Dr. Matthew Oetjens for helpful discussions on the confirmation of exome copy number variations calls using genotyping array. We thank Dr. Natasha Strande for critical comments on the manuscript. We thank the ClinGen Monogenic Diabetes Variation Curation Expert Panel for helpful discussions regarding this variant. Funding Information: This work was financially supported by a grant from the Dutch Kidney Foundation to JHF de B (Large Kolff grant 17OKG07) and JGJH (IMAGEN project which is cofunded by the PPP Allowance made available by Health∼Holland, Top Sector Life Sciences & Health, LSHM20009). KAP has a Career Development fellowship funded by the Wellcome Trust (219606/Z/19/Z). For the purpose of open access, the authors have applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. PI is supported by an NIH grant R01DK042921. Funding Information: The authors would like to acknowledge the participants of the MyCode Community Health Initiative for use of their genomic and electronic health information, without whom this study would not be possible. The patient enrollment and exome sequencing were funded by the Regeneron Genetics Center. We thank the Geisinger-Regeneron DiscovEHR Collaboration for making the genotype data and phenotype available for this project. We are grateful to the laboratory of Dr. Tooraj Mirshahi for the use of the genetic database. We thank Dr. Matthew Oetjens for helpful discussions on the confirmation of exome copy number variations calls using genotyping array. We thank Dr. Natasha Strande for critical comments on the manuscript. We thank the ClinGen Monogenic Diabetes Variation Curation Expert Panel for helpful discussions regarding this variant. Publisher Copyright: {\textcopyright} 2022 International Society of Nephrology",

year = "2022",

month = sep,

doi = "10.1016/j.ekir.2022.06.014",

language = "English (US)",

volume = "7",

pages = "2047--2058",

journal = "Kidney International Reports",

issn = "2468-0249",

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TY - JOUR

T1 - Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification

AU - Mirshahi, Uyenlinh L.

AU - Bhan, Ahana

AU - Tholen, Lotte E.

AU - Fang, Brian

AU - Chen, Guoli

AU - Moore, Bryn

AU - Cook, Adam

AU - Anand, Prince Mohan

AU - Patel, Kashyap

AU - Haas, Mary E.

AU - Lotta, Luca A.

AU - Igarashi, Peter

AU - de Baaij, Jeroen H.F.

AU - Ferrè, Silvia

AU - Hoenderop, Joost G.J.

AU - Carey, David J.

AU - Chang, Alexander R.

N1 - Funding Information: The authors would like to acknowledge the participants of the MyCode Community Health Initiative for use of their genomic and electronic health information, without whom this study would not be possible. The patient enrollment and exome sequencing were funded by the Regeneron Genetics Center. We thank the Geisinger-Regeneron DiscovEHR Collaboration for making the genotype data and phenotype available for this project. We are grateful to the laboratory of Dr. Tooraj Mirshahi for the use of the genetic database. We thank Dr. Matthew Oetjens for helpful discussions on the confirmation of exome copy number variations calls using genotyping array. We thank Dr. Natasha Strande for critical comments on the manuscript. We thank the ClinGen Monogenic Diabetes Variation Curation Expert Panel for helpful discussions regarding this variant. Funding Information: This work was financially supported by a grant from the Dutch Kidney Foundation to JHF de B (Large Kolff grant 17OKG07) and JGJH (IMAGEN project which is cofunded by the PPP Allowance made available by Health∼Holland, Top Sector Life Sciences & Health, LSHM20009). KAP has a Career Development fellowship funded by the Wellcome Trust (219606/Z/19/Z). For the purpose of open access, the authors have applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. PI is supported by an NIH grant R01DK042921. Funding Information: The authors would like to acknowledge the participants of the MyCode Community Health Initiative for use of their genomic and electronic health information, without whom this study would not be possible. The patient enrollment and exome sequencing were funded by the Regeneron Genetics Center. We thank the Geisinger-Regeneron DiscovEHR Collaboration for making the genotype data and phenotype available for this project. We are grateful to the laboratory of Dr. Tooraj Mirshahi for the use of the genetic database. We thank Dr. Matthew Oetjens for helpful discussions on the confirmation of exome copy number variations calls using genotyping array. We thank Dr. Natasha Strande for critical comments on the manuscript. We thank the ClinGen Monogenic Diabetes Variation Curation Expert Panel for helpful discussions regarding this variant. Publisher Copyright: © 2022 International Society of Nephrology

PY - 2022/9

Y1 - 2022/9

N2 - Introduction: Monogenic causes in over 300 kidney-associated genes account for approximately 12% of end stage kidney disease (ESKD) cases. Advances in sequencing and large customized panels enable the noninvasive diagnosis of monogenic kidney disease at relatively low cost, thereby 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 diagnostic testing for a kidney transplant candidate. Methods: A blueprint was designed by a multidisciplinary team of clinicians, molecular biologists, and diagnostic geneticists. The blueprint included using a health system-based cohort with genetic and clinical information to perform deep phenotyping of VUS heterozygotes to identify the candidate VUS and rule out other VUS, examination of existing genetic databases, as well as functional testing. Results: Our approach demonstrated 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 noncarriers. Conclusion: 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 to other diseases of genetic etiology.

AB - Introduction: Monogenic causes in over 300 kidney-associated genes account for approximately 12% of end stage kidney disease (ESKD) cases. Advances in sequencing and large customized panels enable the noninvasive diagnosis of monogenic kidney disease at relatively low cost, thereby 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 diagnostic testing for a kidney transplant candidate. Methods: A blueprint was designed by a multidisciplinary team of clinicians, molecular biologists, and diagnostic geneticists. The blueprint included using a health system-based cohort with genetic and clinical information to perform deep phenotyping of VUS heterozygotes to identify the candidate VUS and rule out other VUS, examination of existing genetic databases, as well as functional testing. Results: Our approach demonstrated 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 noncarriers. Conclusion: 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 to other diseases of genetic etiology.

KW - HNF1B-MODY

KW - autosomal dominant tubulointerstitial kidney disease (ADTKD)

KW - chronic kidney disease

KW - genetics

KW - hypomagnesemia

KW - pancreatitis

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Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification

Abstract

Bibliographical note

Keywords

UN SDGs

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