TRPM4 mutations to cause autosomal recessive and not autosomal dominant Brugada type 1 syndrome |
| |
| Affiliation: | 1. Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad India;2. Asian Institute of Gastroenterology Hyderabad, India;1. Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy;2. Cardiovascular Research Center, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, UK;3. Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy;4. Genetic Unit, Careggi University Hospital, Florence, Italy;5. Department NEUROFARBAUniversity of Florence, Firenze, Italy;6. National Heart Centre, Singapore, Singapore;7. Duke–National University of Singapore Medical School, Singapore, Singapore;1. Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87-00152 Rome, Italy;2. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy;3. Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy;4. Biostatistic Unit, Regina Elena National Cancer Institute, Rome, Italy;5. Cardiomyopathies Unit, Division of Cardiology and Cardiac Arrhythmias, San Camillo-Forlanini Hospital, Rome, Italy |
| |
| Abstract: | Cardiac channelopathies, mainly Long QT and Brugada syndromes, are genetic disorders for which genotype/phenotypes relationships remains to be improved. To provide new insights into the Brugada syndrome pathophysiology, a mutational study was performed on a 64-year-old man presented with isolated exertional dyspnea (NYHA class: II-III), hypertension, chronic kidney disease, coronary disease, an electrocardiogram suggesting a Brugada type 1-like pattern with ST-segment elevation in leads V1-V2. Molecular diagnosis study was performed using molecular strategy based on the sequencing of a panel of 19 Brugada-associated genes. The proband was carrier of 2 TRPM4 null alleles [IVS9+1G > A and p. Trp525X] resulting in the absence of functional hTRPM4 proteins. Due to this unexpected genotype, meta-analysis of previously reported TRPM4 variations associated with cardiac pathologies was performed using ACMG guidelines. All were detected in a heterozygous status. This additional meta-analysis indicated that most of them could not be considered definitely as pathogen. In conclusion, our study reports, for the first time, identification of compound heterozygous TRPM4 null mutations in a proband with, at an arrhythmogenic level, only a Brugada type 1-like electrocardiogram. By combining the genotype/phenotype relationship of this case and analysis of previously reported TRPM4 variations, we suggest that loss-of-function TRPM4 variations, in a heterozygous status, could not be considered as pathogenic or likely pathogenic mutations in cardiac channelopathies such as Long QT syndrome or Brugada syndrome. |
| |
| Keywords: | Brugada syndrome Arrhythmia disorders Truncating mutations Molecular diagnosis Cardiac channelopathies |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
