Dilated and arrhythmogenic cardiomyopathy

Gene: DSG2

Green List (high evidence)

Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in DSG2 gene with arrhythmogenic right ventricular cardiomyopathy. There are also two biallelic cases reported with dilated cardiomyopathy.

The GMS Cardiology Specialist Group decided that all green genes that are present on the Arrhythmogenic right ventricular cardiomyopathy panel should also be green on this panel due to possible phenotypic overlap.

Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.

Created: 4 Sep 2026, 5:28 p.m. | Last Modified: 4 Sep 2026, 5:28 p.m.

Panel Version: 4.11

Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877).

Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC):

PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed).

PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting".

PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain.

PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone.

PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing.

PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.

Below are reported cases with biallelic variants and dilated cardiomyopathy:

PMID:18678517 (2008) reported a single index case with dilated cardiomyopathy and carried a homozygous DSG2 p.Val55Met/ p.Val56Met variant, with an affected father and an asymptomatic mother both identified as heterozygous carriers. A broader cohort screen of 538 idiopathic DCM patients found 13 additional heterozygous carriers versus 3 in 617 controls.

PMID:33949662 (2021) reported the identification of a homozygous p.Arg119Ter variant in a patient with juvenile-onset severe biventricular heart failure, for which iPSC-cardiomyocyte modeling showed disrupted desmosome deposition and abnormal intercalated discs.

Created: 4 Sep 2026, 2:39 p.m. | Last Modified: 4 Sep 2026, 2:55 p.m.

Panel Version: 4.8

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Arrhythmogenic right ventricular dysplasia 10, OMIM:610193; arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Cardiomyopathy, dilated, 1BB, OMIM:612877; dilated cardiomyopathy 1BB, MONDO:0013030

Publications

• 16773573
• 18678517
• 28818065
• 30454721
• 31645976
• 33949662
• 37288269
• 39706847

Green List (high evidence)

On CGGL Royal Brompton DCm panel. Definitive ARVC gene, appropriate for DCM panel due to possible phenotypic overlap

Created: 19 Sep 2019, 8:57 p.m. | Last Modified: 19 Sep 2019, 8:57 p.m.

Panel Version: 0.44

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

Green List (high evidence)

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

Created: 3 Dec 2019, 2:28 p.m. | Last Modified: 3 Dec 2019, 2:28 p.m.

Panel Version: 0.52

DSG2 is a green gene on the Arrhythmogenic cardiomyopathy (code: 134, version 1.25). It has been promoted from amber to green in this panel as the GMS Cardiology Specialist Group decided that all green genes that are present on the Arrhythmogenic cardiomyopathy panel should also be green on this panel because of the overlap in clinical presentation.

Created: 4 Sep 2019, 10:51 a.m. | Last Modified: 4 Sep 2019, 10:51 a.m.

Panel Version: 0.37

Green List (high evidence)

Arrhythmogenic right ventricular dysplasia 10 (610193); Cardiomyopathy, dilated, 1BB (612877)

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

PubMED: 29567486 - core gene. Lots of entries on HGMDPro for ARVC - including good evidence. One C4 reported at BGL.

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.

Green List (high evidence)

Gene currently tested on Manchester cardiac gene panel. 132 variants listed on HGMD (accessed 29/01/2019). ClinGen Knowledge Base: association with arrhythmogenic right ventricular dysplasia 11 (accessed 29/01/2019).

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

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

Phenotypes
Arrhythmogenic right ventricular dysplasia 10 (610193); Cardiomyopathy, dilated, 1BB (612877)

Publications

• 23500315
• 27532257

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

Green List (high evidence)

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

Green List (high evidence)