Can Genetic Profile of Patients Undergoing Heart Transplantation Alter Clinical Decisions?

Abstract

Although a significant proportion of cardiomyopathies are determined by genetic factors, the genetic testing of these patients has not been introduced routinely into clinical practice. The aim of this study is the genotyping of patients with advanced cardiomyopathy who have been bridged for heart transplantation or have been already transplanted, in order to evaluate the usefulness of genetic testing in the early diagnosis of the disease, and in the clinical management of these patients and their relatives. Fifteen heart transplanted patients and 5 patients bridged for heart transplantation due to familial dilated, hypertrophic or restrictive cardiomyopathy were genotyped with next generation sequencing, using Illumina's Trusight Cardio sequencing panel, covering 174 clinically relevant genes to cardiac diseases. Detected variants were characterized according to the recommendations of the American College of Medical Genetics and Genomics. Fifteen patients (75%) were found positive for rare single mutations after genotyping. Nine of these mutations (45% of patients) in PLN, LAMP2, RBM20, TNNI3, LMNA and TTN genes were characterized as pathogenic or likely pathogenic and 7 of them were previously described in the literature. A new likely pathogenic mutation in LMNA gene (p.Arg50Cys) and a new frameshift mutation in TTN gene characterized as pathogenic (p.Ile29015Thr*15), were identified in two families with DCM. The PLN gene mutation (p.Leu39*) was detected in 3 of the 20 patients (15%) indicating that it could be a founder mutation in the Greek population. Six patients (30%) carried variants of unknown significance (vus), while 5 patients (25%) didn't harbor any mutation. One of the vus in the TPM1 gene is of great interest since it was detected in three heart transplanted members of a DCM family. A significant proportion of rare variants in genes associated with cardiomyopathies has been identified in a cohort of patients undergoing heart transplantation. Detection of these variants may be critical in early diagnosis and management of the patient and his family and might prevent sudden cardiac death or alter heart transplantation or VAD implantation clinical decisions.