Progressive cardiac conduction disease

Gene: TRPM4

I don't know

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.

Created: 2 Dec 2019, 10:38 a.m. | Last Modified: 2 Dec 2019, 10:38 a.m.

Panel Version: 0.30

Green List (high evidence)

Associated with conduction disease in the literature and on OMIM.

Created: 25 Sep 2019, 2:30 p.m. | Last Modified: 25 Sep 2019, 2:30 p.m.

Panel Version: 0.28

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Progressive familial heart block, type IB 604559

Publications

• 29568272
• 29748318
• 30021168
• 20562447

I don't know

Green List (high evidence)

Progressive familial heart block, type IB (604559)

Created: 25 Mar 2019, 4:30 p.m.

In cellular expression systems, mutant TRPM4 channels produce a larger current than wt (GoF). 4 families identified. Hypothesised GoF mutant channels lead to cell membrane depolarisation in the conduction system, therefore reducing number of Na channels and resulting in conduction abnormality. Functional experiments expressing these three mutant variants of TRPM4 suggested a similar gain-of-function phenomenon related to altered deSUMOylation 21887725. 20562447

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

I don't know

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

Comment on list classification: Promoted from Red to Amber due to review from the Oxford Medical Genetics Laboratory, provided by Kate McGuire.

Created: 25 Jan 2019, 11:57 a.m.

Green List (high evidence)

AMBER GENE - Moderate evidence. Liu et al 2010 - report 3 variants that segregate in large kindreds. However, 2 of these variants (G844D and A432T) almost meet ACMG benign criteria (0.2% and 0.09% in gnomAD populations). Stallmeyer et al 2012 - 4 small pedigrees where variants segregate with a consistent phenotype. Most variants appear to be potentially pathogenic i.e. functionally significant part of protein, not in controls / populations, segregate with phenotype, supportive in silico predictions. Previously reported G844D variant found in 2 x probands and their unaffected (normal ECG) parent. Kruse et al 2009 - report segregation of a potentially pathogenic variant in 35 individuals of a large Afrikaner kindred who are affected with cardiac conduction abnormalities. Variant not in a known functionally significant part of the protein but not in populations and in vitro studies support a pathogenic effect.

Created: 25 Jan 2019, 11:55 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
PROGRESSIVE FAMILIAL HEART BLOCK,

Publications

• 19726882
• 20562447
• 21887725