Developing a genetic testing panel for evaluation of morbidities in kidney transplant recipients

Becky M Ma; Naama Elefant; Martina Tedesco; Kelsie Bogyo; Natalie Vena; Sarath K Murthy; Shiraz A Bheda; Sandy Yang; Nikita Tomar; Jun Y Zhang; Syed Ali Husain; Sumit Mohan; Krzysztof Kiryluk; Hila Milo Rasouly; Ali G Gharavi

doi:10.1016/j.kint.2024.02.021

Developing a genetic testing panel for evaluation of morbidities in kidney transplant recipients

Kidney Int. 2024 Mar 21:S0085-2538(24)00188-1. doi: 10.1016/j.kint.2024.02.021. Online ahead of print.

Authors

Affiliations

¹ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA; Department of Medicine, Center for Precision Medicine and Genomics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Division of Nephrology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
² Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA; Department of Medicine, Center for Precision Medicine and Genomics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
³ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA; Department of Medicine, Center for Precision Medicine and Genomics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.
⁴ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.
⁵ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA; Department of Medicine, Center for Precision Medicine and Genomics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA. Electronic address: ag2239@cumc.columbia.edu.

PMID: 38521406
DOI: 10.1016/j.kint.2024.02.021

Abstract

Cardiovascular disease, infection, malignancy, and thromboembolism are major causes of morbidity and mortality in kidney transplant recipients (KTR). Prospectively identifying monogenic conditions associated with post-transplant complications may enable personalized management. Therefore, we developed a transplant morbidity panel (355 genes) associated with major post-transplant complications including cardiometabolic disorders, immunodeficiency, malignancy, and thrombophilia. This gene panel was then evaluated using exome sequencing data from 1590 KTR. Additionally, genes associated with monogenic kidney and genitourinary disorders along with American College of Medical Genetics (ACMG) secondary findings v3.2 were annotated. Altogether, diagnostic variants in 37 genes associated with Mendelian kidney and genitourinary disorders were detected in 9.9% (158/1590) of KTR; 25.9% (41/158) had not been clinically diagnosed. Moreover, the transplant morbidity gene panel detected diagnostic variants for 56 monogenic disorders in 9.1% KTRs (144/1590). Cardiovascular disease, malignancy, immunodeficiency, and thrombophilia variants were detected in 5.1% (81), 2.1% (34), 1.8% (29) and 0.2% (3) among 1590 KTRs, respectively. Concordant phenotypes were present in half of these cases. Reviewing implications for transplant care, these genetic findings would have allowed physicians to set specific risk factor targets in 6.3% (9/144), arrange intensive surveillance in 97.2% (140/144), utilize preventive measures in 13.2% (19/144), guide disease-specific therapy in 63.9% (92/144), initiate specialty referral in 90.3% (130/144) and alter immunosuppression in 56.9% (82/144). Thus, beyond diagnostic testing for kidney disorders, sequence annotation identified monogenic disorders associated with common post-transplant complications in 9.1% of KTR, with important clinical implications. Incorporating genetic diagnostics for transplant morbidities would enable personalized management in pre- and post-transplant care.

Keywords: diagnostics; exome sequencing; kidney transplantation; precision medicine.