Abstract
Progressive cardiac conduction disease (PCCD) is a relatively common condition in young and elderly populations, related to rare mutations in several genes, including SCN5A, SCN1B, LMNA and GJA5, TRPM4. Familial cases have also been reported. We describe a family with a large number of individuals necessitating pacemaker implantation, likely due to varying degrees of PCCD. The proband is a 47-year-old-patient, whose younger brother died at 25 years of unexplained sudden cardiac death. Three paternal uncles needed a pacemaker (PM) implantation between 40 and 65 years for unspecified causes. At the age of 42, he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB). NGS analysis revealed the missense variation c. 2351G>A, p.Gly844Asp in the exon 17 of the TRPM4 gene. This gene encodes the TRPM4 channel, a calcium-activated nonselective cation channel of the transient receptor potential melastatin (TRPM) ion channel family. Variations in TRPM4 have been shown to cause an increase in cell surface current density, which results in a gain of gene function. Our report broadens and supports the causative role of TRPM4 gene mutations in PCCD. Genetic screening and identification of the causal mutation are critical for risk stratification and family counselling.
Highlights
Progressive cardiac conduction disorder (PCCD) is an inherited cardiac disease that may present as a primary electrical disease or in association with structural heart diseases, and often requires pacemaker (PM) implantation [1]
The pathogenesis of the inherited PCCD in structurally normal hearts was linked to genetic variants in the ion channel genes SCN5A, SCN1B, SCN10A, TRPM4 and KCNK17 as well as in genes coding for cardiac connexin proteins, such as GJA5, associated with lone atrial fibrillation
A proband with 1st degree atrioventricular block (AVB) associated with complete right bundle branch3 of block (RBBB) and a history of syncope was investigated by NGS analysis
Summary
Progressive cardiac conduction disorder (PCCD) is an inherited cardiac disease that may present as a primary electrical disease or in association with structural heart diseases, and often requires pacemaker (PM) implantation [1]. Mutations in the two above mentioned genes may cause cardiac cond disorders associated with various congenital heart defects. Inherited mutations in the TRPM4 gene are associated with PFHBI and isolated cardiac conduction disease Genes 2022(,I1C3,C25D8 ), giving rise to the atrio-ventricular conduction block (AVB), right bundle branch of 9 block (RBBB), bradycardia, and Brugada syndrome. He was hythpeepratteiennstirveep.ort that he was diagnosed with extreme bradycardia and high risk of cardiac The proband,arcruesrtrednutrliyng4a7c, airsdtiohleogfiicrscht eocfk-tuhprefoersdiybslpinngeas,, aanldl mwaasleims,mthedeialtaeslyt oimf pwlahnotemd. The proband, currently 47, is the first of three siblings, all males, the last of whom died in his sleep at the age of 25 (Figure 2)
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