Searching for genetic modulators of the phenotypic heterogeneity in Brugada syndrome

• Published in: PloS one 2022-01, Vol.17 (3)
• Main Authors: Laura Martínez-Campelo, Raquel Cruz, Alejandro Blanco-Verea, Isabel Moscoso, Eva Ramos-Luis, Ricardo Lage, María Álvarez-Barredo, María Sabater-Molina, Pablo Peñafiel-Verdú, Juan Jiménez-Jáimez, Moisés Rodríguez-Mañero, María Brion
• Format: Article
• Language: English
• ISSN: 1932-6203

In Brugada syndrome, even within the same family where all affected individuals share the same mutation, phenotypic variation is prominent, with variable penetrance and expressivity, presenting different degrees of involvement. It is difficult to establish a direct correlation between genotype and phenotype to predict prognosis in complications and risk of sudden death. The factors that modulate this inter- and intra-familial phenotypic variability remain to be determined. With the intention of testing whether other genetic factors, in addition to the causal mutation in SCN5A, may have a modulating effect on the Brugada phenotype and the risk of sudden death, we have studied 8 families with a causal variant in SCN5A with at least two affected individuals, one of whom has suffered cardiac arrest or sudden death. Whole exome sequencing was performed looking for additional variants that modify the phenotype and allow us to predict a better or worse prognosis for the evolution of the disease. The results did not show any clear genetic modifier; nevertheless, highlight the possible implication of the cholesterol and fibrosis pathways, as well as the circadian rhythm, as possible modulators of Brugada syndrome phenotype.