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Dilated and arrhythmogenic cardiomyopathy v4.11 DSG2 Achchuthan Shanmugasundram Added comment: 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.
Dilated and arrhythmogenic cardiomyopathy v4.11 DSG2 Achchuthan Shanmugasundram Mode of inheritance for gene: DSG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v4.10 DSG2 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: DSG2.
Tag Q3_26_MOI tag was added to gene: DSG2.
Dilated and arrhythmogenic cardiomyopathy v4.10 DSG2 Achchuthan Shanmugasundram Publications for gene: DSG2 were set to 23500315; 27532257
Dilated and arrhythmogenic cardiomyopathy v4.9 DSG2 Achchuthan Shanmugasundram Phenotypes for gene: DSG2 were changed from Arrhythmogenic right ventricular dysplasia 10; Arrhythmogenic right ventricular dysplasia 10 (610193); Cardiomyopathy, dilated, 1BB (612877) to Arrhythmogenic right ventricular dysplasia 10, OMIM:610193; arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Cardiomyopathy, dilated, 1BB, OMIM:612877; dilated cardiomyopathy 1BB, MONDO:0013030
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram edited their review of gene: DSG2: Changed publications to: 16773573, 18678517, 28818065, 30454721, 31645976, 33949662, 37288269, 39706847
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram changed review comment from: 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.; to: 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.
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram changed review comment from: 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 not in OMIM or ClinGen.

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.; to: 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.
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram edited their review of gene: DSG2: Changed phenotypes to: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434, Cardiomyopathy, dilated, 1BB, OMIM:612877, dilated cardiomyopathy 1BB, MONDO:0013030
Dilated and arrhythmogenic cardiomyopathy v4.8 DSG2 Achchuthan Shanmugasundram reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16773573, 28818065, 30454721, 31645976, 37288269, 39706847; Phenotypes: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v0.52 DSG2 Ivone Leong commented on gene: DSG2: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.
Dilated and arrhythmogenic cardiomyopathy v0.44 DSG2 Matthew Edwards reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Dilated and arrhythmogenic cardiomyopathy v0.37 DSG2 Ivone Leong reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated and arrhythmogenic cardiomyopathy v0.36 DSG2 Ivone Leong gene: DSG2 was added
gene: DSG2 was added to Dilated cardiomyopathy - adult and teen. Sources: Expert Review Green,Expert List
Mode of inheritance for gene: DSG2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DSG2 were set to 23500315; 27532257
Phenotypes for gene: DSG2 were set to Arrhythmogenic right ventricular dysplasia 10; Arrhythmogenic right ventricular dysplasia 10 (610193); Cardiomyopathy, dilated, 1BB (612877)