Brugada syndrome and cardiac sodium channel disease

Gene: HCN4

Comment on phenotypes: This gene is also associated with Sick sinus syndrome 2 (163800)

Created: 2 Mar 2021, 11:48 a.m. | Last Modified: 2 Mar 2021, 11:48 a.m.

Panel Version: 2.14

Green List (high evidence)

Brugada syndrome 8 (OMIM 613123), Sick sinus syndrome 2 (OMIM 163800)

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

Milano (2014) paper (25145517) showed segregation / ?functional effect. Macri paper (24607718) showed functional effect. PMID: 27553229. https://ac.els-cdn.com/S0735109716015862/1-s2.0-S0735109716015862-main.pdf?_tid=89c56f79-58d9-413a-a162-598c96f24a0b&acdnat=1546869351_0c665867a80ab79d2af032616efe9099

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

Red List (low evidence)

Comment on list classification: Due to new expert reviews and disputed evidence for this gene-disease causation, this gene has been demoted from Green to Red.

Created: 27 Feb 2019, 9:58 a.m.

This gene was given a validity classification of Disputed by the ClinGen validity curation group and is reflected by providing a Red review here.The gene-disease summary was downloaded on 20th Feb 2019.For the full report and publications see the ClinGen Gene Validity Curation for each gene here: https://search.clinicalgenome.org/kb/gene-validity/10150

Created: 20 Feb 2019, 2:47 p.m.

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.

Mode of inheritance
Disputed

Phenotypes
Brugada syndrome 1; MONDO_0011001

Red List (low evidence)

Gene currently tested on Manchester cardiac gene panel. Only class 1-3 variants detected to date. 37 variants listed on HGMD (accessed 29/01/2019). ClinGen Knowledge Base: disputed association with Brugada syndrome 1 (accessed 29/01/2019).

Created: 14 Feb 2019, 1:38 p.m.

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

Phenotypes
Brugada syndrome 8 (613123); Sick sinus syndrome 2 (163800)

Publications

• 27761167

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

Comment when marking as ready: On Manchester diagnostic panel

Created: 11 Feb 2016, 11:16 a.m.

Red List (low evidence)

Mouse studies suggest homozygous knockout is embryonic lethal. Heterozygous littermates were phenotypically indistinguishable from WT. Most variants reported are in sick sinus syndrome or with sinus bradycardia. 2 variants id in this gene in isolated cases of brugada syndrome (1 was asymptomatic) - minimal evidence suggesting pathogenicity for BS. Suggest Red gene for BS - Green gene for sick sinus syndrome - Green gene on molecular autopsy panel.

Created: 25 Jan 2019, 1:15 p.m.

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