DSG2

Gene Facts

• HGNC Symbol: DSG2 (HGNC:3049)
• HGNC Name: desmoglein 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: CDHF5
• %HI: 62.78
• pLI: 0
• LOEUF: 0.76
• Cytoband: 18q12.1
• Genomic Coordinates:

  GRCh37/hg19:	chr18:29078140-29128971
  GRCh38/hg38:	chr18:31498177-31549008

• MANE Select Transcript: NM_001943.5 ENST00000261590.13
• Function: Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-5097
• ClinGen Curation ID: CCID:007037
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Emerging Evidence for Haploinsufficiency (2)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
  Incomplete penetrance and variable expressivity is noted in many papers.
• Last Evaluated: 12/13/2022

Haploinsufficiency (HI) Score Details

• HI Score: 2
• HI Evidence Strength: Emerging Evidence for Haploinsufficiency

HI Disease

• Arrhythmogenic right ventricular dysplasia 10

HI Evidence

• PUBMED: 21397041
  Lahtinen et al. (2011) identified a proband with ARVC who had a novel 3059_3062delAGAG frameshift mutation leading to abolishing 99 carboxy-terminal amino acids of desmoglein-2. This mutation was found in four additional family members: two of whom met minor criteria for first-degree family members, one had minor repolarization abnormalities, and the fourth was unaffected. A screen for this mutation in the control samples revealed one carrier who then was found to have a conduction defect. Since the immunoreactive signal for desmoglein-2 was reduced by over 50%, a dominant-negative effect for the mutation was suggested as a possibility.
• PUBMED: 17105751
  Syrris et al (2007) investigated 86 Caucasian ARVC patients for mutations in DSG2 by direct sequencing and detected eight novel mutations in nine probands (who did not have mutations in the other three desmosomal genes associated with the disease). Clinical evaluation of family members with DSG2 mutations demonstrated penetrance of 58% using Task Force criteria, or 75% using proposed modified criteria. Of the 8 mutations: there were 5 missense mutations (all in functionally important regions of the gene), a 3G > C mutation which is predicted to abolish translation initiation, a 829_840delCTTGAAGGGATG splice site variant. The splice site variant was detected in a 15 year old who died suddenly (the variant was also detected in the proband's mum and brother who both had features of ARVC) and the 3G > C variant was also detected in 2 affected family members (His father was a carrier and had clinical features suggestive of disease expression and one paternal second cousin and his three sons were also mutation carriers presenting with variable disease expression. There was also a nonsense variant (1773_1774delTG) resulting in a premature termination codon (C591X) in the extracellular anchor domain of the DSG2 protein.
• PUBMED: 16773573
  Awad et al (2006) identified four patients with ARVD/C with mutations in DSG2. One proband had two mutations in trans, a missense c.143G>A (R48H) on his paternal allele and a c.915G>A change resulting in a premature termination codon, W305X, in exon 8 of his maternal allele. Of note, his 77-year-old mother was found to carry the same nonsense mutation, but was unaffected based upon extensive clinical assessments. His 24 year-old sister also carries the W305X mutation and is believed to be unaffected. His father who presumably passed on the R48H mutation died due to non-cardiac issues at age 74 and was never tested. The remaining three probands in this study had a single, heterozygous missense mutation each: c.134G>A (R45Q), c.1517G>A (C506Y), and c.2431G>T (G811C). Of note, the mother of the proband with R45Q and the mother of the proband with G811C were both found to be carriers of their respective familial mutation and were determined to be unaffected after extensive cardiac assessments. Discussion regarding mutational mechanism included the possibility of both haploinsufficiency and dominant-negative as possible mechanisms.
• PUBMED: 31638835
  Carruth et al (2019) screened for putative LOF variants in PKP2, DSC2, DSG2, and DSP from whole exome sequencing of 61,019 individuals in the DiscovEHR cohort. They found 13 predicted LOF DSG2 variants and one missense variant. The LOF variants included 5 splice site, 3 nonsense and 5 frameshift variants. One splice site variant was detected in 6 individuals (c.523+1_523+2del), a c.1109dup frameshift was detected in 8 individuals and a c.1487dup frameshift was detected in 13 individuals. 6 of the LOF variants were associated with an ARVC diagnosis. Incomplete penetrance is noted. No inheritance information provided.
• PUBMED: 29606362
  Amalio Ruiz Salas et al (2018) performed an observational, retrospective cohort study, which included 36 patients diagnosed with high-risk ARVC in their hospital over a 17 year period. Genetic analysis was performed using next-generation sequencing. They found 5 DSG2 variants including 2 nonsense variants.
• PUBMED: 16505173
  Pilichou et al (2006) reported on a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-β3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions (1253 to 1257insATGA, 2036delG), 1 nonsense (1672C>T), and 1 splice site mutation (1881 to 2A→G)) were detected in 8 proband (in 1 patient, 2 different mutations (E331K and 1881 to 2A→G) were detected in trans). None of the detected variants were found in controls.

• HI Evidence Comments: Desmoglein-2 (DSG2) has been associated with autosomal recessive and dominant cardiac phenotypes. DSG2 is a member of the desmoglein family and is expressed in myocardium. DSG2 is an essential component of the desmosome so mutations of this gene disrupt the proper organization of desmosomal junctions. Mutations of DSG2 and other desmosomal genes have been demonstrated to be associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), but the phenotype is widely variable ranging from individuals who meet strict diagnostic criteria to those who are asymptomatic and identified in control populations. Some affected patients have compound heterozygous mutations. So variants in DSG2 might be susceptibility variants, rather than pathogenic variants. Also, digenic, homozygous, and compound heterozygous inheritance has been suggested. While several putative loss of function variants have been described, the mechanism by which these mutations cause disease has not been clearly determined and no patients with complete gene deletions and ARVD/C have been reported. However, Brodehl et al (2021) suggest continuing 'dynamic clinical investigations of heterozygous mutation carriers in the future as long as possible because we cannot exclude that a cardiac phenotype will occur'. Also see PMID: 33917638 Brodehl et al (2021) report two families with recessive inheritance of loss of function DSG2 variants. Despite the recessive type of inheritance in both their families they suggest continued dynamic clinical investigations of heterozygous mutation carriers as long as possible because a later onset cardiac phenotype cannot be excluded. PMID: 26296472 Zhang et al. (2015) obtained DNA from post-mortem heart tissues, 25 patients had ARVC as a cause of death while the other 25 had sudden unexplained death. Two novel mutations in DSG2 were identified in each group. A frameshift insertion c.3075_3076insC (S1026Q fsX12) and a missense c.2032G>A (G678R) mutation was found in the ARVC group. In the samples from patients with sudden unexplained death, the missense mutations were c.2686G>A (E896K) and c.2573C>T (A858V). None of these variants was found in 96 control samples. No commentary as to possible mutation mechanism was included.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity