Progressive Familial Heart Block via the TRPM4 Gene

Progressive familial heart block is a genetic condition that alters the normal beating of the heart. It can be divided into type IA, type IB and type II, based on the location of heart signaling interruption and the genetic cause. In types IA and IB, the heart block originates in the bundle branch, and in type II, the heart block originates in the atrioventricular node (Fernandez et al. 2004; Lee et al. 2011).

Progressive familial heart block type I (PFHBI) is an autosomal dominant cardiac bundle branch disease that may progress to complete heart block. In electrocardiograph, PFHBI could be indicated by right bundle branch block, left anterior or posterior hemiblock, or complete heart block, with broad QRS complexes (Daumy et al. 2016). Affected people may have shortness of breath, dizziness, fainting, heart failure, or sudden death. The implantation of a pacemaker or electrocardiographic follow-up are treatment options. Progressive familial heart block type IB (PFHB1B) is caused by heterozygous pathogenic variants in the TRPM4 gene (Liu et al. 2010).

Pathogenic variants in TRPM4 lead to Progressive Familial Heart Block type 1B (PFHB1B), which is inherited in an autosomal dominant pattern. TRPM4 encodes the Ca2+-activated nonselective cation channel of the transient receptor potential melastatin ion channel family and contains 25 exons, encodes 1214 amino acids and spans over 54 kb in Chromosome 19q13.33. TRPM4 transcripts can be detected ubiquitously in the human heart and, in particular, within the Purkinje fibers, a key structure for cardiac conduction. Pathogenic variants increase current density due to an elevated TRPM4 channel density at the cell surface secondary to impaired endocytosis and deregulation of SUMOylation (Kruse et al. 2009; Liu et al. 2010). So far, all reported pathogenic variants in TRPM4 are single nucleotide substitutions (missense or nonsense) (Human Gene Mutation Database).

Pathogenic variants in TRPM4 were identified in ~5% of unrelated heritable arrhythmia probands with various ECG phenotypes (Stallmeyer et al. 2012).

This test provides full coverage of all coding exons of the TRPM4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).