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

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.

Figure 1.. Three gene lists used in the study.

The total number of genes and number of overlapped genes between the transplant morbidity panel, Mendelian kidney and genitourinary disorders panel, and ACMG secondary findings gene list shown in Venn diagram. ACMG, American College of Medical Genetics.

Figure 2.. Diagnostic yield of the transplant morbidity panel.

(A) The distribution of kidney transplant recipients with diagnostic variants stratified by categories of post-transplant complications. (B) The proportion of kidney transplant recipients with diagnostic variants, stratified by the ACMG secondary findings list. (C) The most common diagnostic genetic findings detected by the transplant morbidity panel. ACMG, American College of Medical Genetics.

Figure 3.. Clinical implications of diagnostic variants detected by the transplant morbidity panel.

Clinical implications of genetic findings in kidney transplant care, stratified by disease categories, with top three genes in each category listed.

Figure 4.. Diagnostic yield of the Mendelian kidney and genitourinary disorders gene panel.

The proportion of kidney transplant recipients with diagnostic variants identified by the Mendelian kidney and genitourinary disorders gene panel, stratified by categories of kidney disease. CAKUT, congenital anomalies of the kidney and urinary tract; SRNS, steroid-resistant nephrotic syndrome.