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Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype–phenotype characterization of familial disease

Petros Syrris, Deirdre Ward, Angeliki Asimaki, Alison Evans, Srijita Sen-Chowdhry, Sian E. Hughes, William J. McKenna
DOI: http://dx.doi.org/10.1093/eurheartj/ehl380 581-588 First published online: 14 November 2006


Aims Mutations in the desmoglein-2 (DSG2) gene have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) but clinical information regarding the associated phenotype is at present limited. In this study, we aimed to clinically characterize probands and family members carrying a DSG2 mutation.

Methods and results We investigated 86 Caucasian ARVC patients for mutations in DSG2 by direct sequencing and detected eight novel mutations in nine probands. Clinical evaluation of family members with DSG2 mutations demonstrated penetrance of 58% using Task Force criteria, or 75% using proposed modified criteria. Morphological abnormalities of the right ventricle were evident in 66% of gene carriers, left ventricular (LV) involvement in 25%, and classical right precordial T-wave inversion only in 26%. Sustained ventricular arrhythmia was present in 8% and a family history of sudden death/aborted sudden death in 66%.

Conclusion Mutations in DSG2 display a high degree of penetrance. Disease expression was of variable severity with LV involvement a prominent feature. The low prevalence of classical ECG changes highlights the need to expand current diagnostic criteria to take account of LV disease, childhood disease expression, and incomplete penetrance.

  • Arrhythmia
  • Cardiomyopathy
  • Cell adhesion molecules
  • Genetics
See page 529 for the editorial comment on this article (doi:10.1093/eurheartj/ehl530)


Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/ARVD) is an inherited heart muscle disorder associated with ventricular arrhythmia, heart failure, and sudden death.1,2 Histologically, it is characterized by fibro-fatty replacement of cardiac myocytes in both ventricles, although RV manifestations predominate in early disease.3 The prevalence of familial ARVC is thought to be at least 30–50%.4 ARVC is a major cause of sudden death in young people3,5 and is typically inherited as an autosomal dominant trait with variable penetrance. Autosomal recessive transmission has also been reported in syndromic forms.6

To date, a number of chromosomal loci have been associated with ARVC6 but only a few disease-causing genes have been identified: plakoglobin, desmoplakin, plakophilin-2, cardiac ryanodine receptor, and transforming growth factor β3 gene.7

Desmosomes are specialized junctions in epithelia and heart muscle that mediate intercellular adhesion and provide tissues with mechanical strength.8 Desmoplakin, plakoglobin, and plakophilin-2 are major components of the desmosome, and their implication in ARVC has fostered the view that impaired cell adhesion is the primary underlying molecular defect. This was further strengthened by two recent studies that reported mutations in the desmosomal desmoglein-2 (DSG2) gene as the cause of familial ARVC.9,10 However, those studies concentrated on the clinical evaluation of probands with DSG2 mutations and provided limited clinical and genetic information on family members.

We have screened 86 consecutive Caucasian patients diagnosed with ARVC (who were free of mutations in desmoplakin, plakoglobin, and plakophilin-2)11 for mutations in DSG2 and have detected eight disease-causing changes in nine probands. We have also clinically characterized these probands as well as family members carrying a DSG2 mutation.


Clinical evaluation

The study was approved by the University College London Hospitals Trust Ethics Committee. Informed consent was obtained from all participating individuals. Clinical evaluation was performed as described before11 and was based on the criteria set forth by the International Task Force of the European Society of Cardiology and International Society and Federation of Cardiology Diagnostic Criteria12 and the Proposed Modified Diagnostic Criteria.13

Mutation screening

Genomic DNA from probands and family members was extracted from whole blood using QIAamp DNA Blood mini kits (Qiagen). All probands had been previously screened for mutations in known desmosomal ARVC genes: desmoplakin, plakoglobin, and plakophilin-2.11 On the basis of published sequences of the DSG2 gene and chromosome 18 (GenBank accession no NM_001943 and AC079096, respectively), primer pairs for all DSG2 exons were designed from flanking intronic sequences. However, comparison of these sequences revealed discrepancies in the reported nucleotide sequence of exon 1. In our study, we have established the exact sequence of the DSG2 gene at the genomic level. It shows that the accurate amino acid sequence of the DSG2 protein is that reported by Whittock et al.14 and therefore numbering of sequence variations given in this study is based on it. PCR amplification was carried out using standard protocols (AmpliTaq Gold, Applied Biosystems) for all fragments except exon 1, which, due to its high GC content, was amplified with GC RICH PCR system (Roche). All primer sequences and PCR conditions are available on request. PCR products were subjected to direct sequencing in both directions on an Applied Biosystems 3130 Genetic Analyzer using BigDye Terminator chemistry (v3.1) and analysed by Seqscape v2.5 software (Applied Biosystems).

A total of 200 unrelated healthy volunteers of the same ethnic origin served as controls.

Microscopic examination of RV specimen

Sections from an RV biopsy from individual III.4 (Family A) obtained during implantation of a cardioverter-defibrillator (ICD) were examined. For light microscopy, specimens were fixed in 10% formalin and processed with paraffin wax. Myocardial tissue sections (4 µm) were cut and stained with haematoxylin and eosin. Myocardial specimens were additionally treated with Masson's trichrome, which stains collagen fibres blue–green, while muscle and other tissue appear red.


Mutations in DSG2

The study population comprised 86 unrelated patients with ARVC who were free of mutations in three desmosomal genes associated with the disease. Screening of the DSG2 gene identified eight heterozygous mutations in nine patients (Table 1).

View this table:
Table 1

Summary of DSG2 mutations

ExonNucleotide changeCoding effectPositionFamily
13G > CM1I predicted abolition of translation initiationStart codon—Signal peptideC
3165G > AV56MEC1 extracellular domainH
5462C > AD154EEC1 extracellular domainD
5473T > GV158GEC1 extracellular domainE, F
8829_840delCTTGAAGGGATGAbnormal splicingEC3 extracellular domainB
91174G > AV392IEC4 extracellular domainI
121773_1774delTGC591XExtracellular anchor domainA
152759T > GV920GRepeat unit domainG

A deletion of two bases in exon 12 of DSG2 (1773_1774delTG) was detected in Family A (Figure 1A). This mutation results in a premature termination codon (C591X) in the extracellular anchor domain of the DSG2 protein.

Figure 1

(A–C) Pedigrees of ARVC families A–F and sequence electropherograms of DSG2 showing mutant sequences compared with a normal control. Squares denote males and circles females. Solid symbols indicate individuals fulfilling International Task Force diagnostic criteria for ARVC12 and/or those confirmed as affected at post-mortem; grey symbols, individuals fulfilling the modified diagnostic criteria only;13 a cross inside a symbol, mutation carriers who have clinical features suggestive of disease expression, but who fulfil neither Task Force nor proposed modified diagnostic criteria; open symbols, unaffected individuals; ‘N’ symbols, individuals who underwent clinical evaluation and had no features of ARVC; dotted symbols, deceased individuals who did not undergo clinical evaluation and considered probably affected because of their position in the pedigree as obligate gene carriers; slanted bars, deceased individuals; + and −, the presence or absence of a DSG2 mutation, respectively; SB, still birth. The index patient in each family is marked with an arrow. Pedigrees shown reflect those nuclear families that were available for evaluation or where available information was verifiable.

A deletion of 12 nucleotides (829_840delCTTGAAGGGATG) was detected in exon 8 in Family B (Figure 1A).

A G → C transversion was found in the start codon of DSG2 in Family C (Figure 1B). This change alters the translation initiation codon ATG to ATC (3G > C) and leads to a substitution of a methionine by isoleucine (Figure 1B).

Five missense mutations were identified in functionally important regions of DSG2. In particular, a C → A transversion in exon 5 resulting in the substitution of an aspartic acid with a glutamic acid (D154E) was found in Family D (Figure 1B). In the same exon, Families E and F had a T → G change which replaces a valine with a glycine at position 158 (V158G), (Figure 1C). Finally, mutations V920G, V56M, and V392I were detected in Families G, H, and I, respectively.

All mutations were absent in 400 control chromosomes.

Clinical findings

Family A (Figure 1A). The proband (III.4), an aerobics teacher, experienced episodes of sustained palpitation and recurrent pre-syncope. Her 12-lead ECG demonstrated sinus rhythm with poor R-wave progression, and inverted T-waves in V1-6 and the inferior leads (Figure 2A). Two-dimensional contrast-enhanced echocardiography identified regional wall motion abnormalities (RWMA) in both ventricles and a left ventricular (LV) apical aneurysm. A cardiovascular magnetic resonance (CMR) study revealed biventricular dilation, structural abnormalities, and multiple RV aneurysms in addition to the LV apical aneurysm (Figure 2B). Ambulatory ECG (Holter) monitoring demonstrated 1400 ventricular extrasystoles in a 24 h period, including a triplet of non-sustained ventricular tachycardia (NSVT). An ICD was implanted. Histology of endomyocardial biopsy from the proband was characteristic of ARVC showing loss of myocardium and replacement by fibroadipose tissue (Figure 3A–D).

Figure 2

(A) Electrocardiogram from individual III.4 (Family A) showing characteristic T-wave inversion, poor R-wave progression, and diminutive voltages in V5-6 consistent with LV involvement. (B) CMR (TrueFISP) images from individual III.4 (Family A), four-chamber view in diastole and systole. The black arrows indicate regions of diastolic bulging and hypokinesia in the right ventricle and LV apex.

Figure 3

Histology of endomyocardial biopsy from individual III.4 (Family A) showing (A) myocytes surrounded by fibrous tissue and sarcoplasmic vacuolization (haematoxylin and eosin staining), (B) myocytes surrounded by fibroadipose tissue and a cluster of adipocytes (haematoxylin and eosin staining), (C) loss of myocardium and fibroadipose substitution (haematoxylin and eosin staining), (D) increase in fibrous tissue (blue–green) in biopsy specimen (modified Masson's trichrome staining).

The proband's mother (II:2, 79 years) was asymptomatic with a normal ECG and conventional two-dimensional echo to the age of 75. However, she did not undergo specific ARVC evaluation due to other medical problems.

The proband's daughter (IV:2, age 11) was asymptomatic. Twelve-lead ECG showed sinus rhythm with T-wave inversion in V1, V2, and a biphasic T-wave in V3. In view of her age, this finding could be considered compatible with a juvenile repolarization pattern and is not valid for inclusion using the current diagnostic criteria. Transthoracic echocardiography, however, was abnormal with an area of hypokinesia in the lateral wall of the right ventricle.

All three individuals were heterozygous for the C591X mutation in DSG2.

Family B (Figure 1A). The proband (III.1) died suddenly, aged 15, with ARVC identified as cause of death on post-mortem. Her brother (III.4), who carries the 829_840delCTTGAAGGGATG mutation, showed widespread T-wave inversion on ECG, LV and RV enlargement and impaired systolic function (LV ejection fraction 25%), a positive signal-averaged ECG and in excess of 3000 ventricular ectopics on Holter monitoring, with salvos of NSVT of predominantly RV origin. He has an ICD which has delivered several appropriate therapies for VT. Despite his systolic impairment, he remains in NYHA functional class II. The proband's mother (II.6) who also carries this deletion in DSG2 had features of ARVC on ECG and contrast-enhanced echocardiography.

Family C (Figure 1B). The proband (IV.4) presented, aged 14, with exertional syncope. He had diagnostic features of ARVC on ECG and imaging with gross biventricular enlargement and severe impairment of systolic function (LV ejection fraction 15–20%) (Table 2). An ICD was implanted following recurrent VT and there was one appropriate discharge 2 years later for ventricular fibrillation (VF). Systolic function has not changed during 10 years of follow-up, and he remains clinically stable (NYHA class II). His father (III.5) had clinical features suggestive of disease expression and carries the 3G > C mutation. Echo showed predominantly LV dilation with mildly impaired systolic function, but also RV wall motion abnormalities. One paternal second cousin (III.1) and his three sons (IV.1—IV.3) are also mutation carriers presenting with variable disease expression.

View this table:
Table 2

Clinical data of ARVC families

IndividualSymptomsFamily historyRepolarization abnormalitiesDepolarization/conduction abnormalitiesRV structural abnormalities on imaging>1000 PVCs on 24 h HolterNSVT/VT/VFDiagnostic criteria
Family A
 III.4 (44 years)Palpitations, presyncope+ (Inf leads V1–V5)+++NSVT2/2a
 II.2 (79 years)Palpitations+0/1
 IV.2 (11 years)None++ (age 11 years)+0/3b
Family B
 III.4 (34 years)Syncope++ (Inf leads, V1–V6)++ (RV + LV)+NSVT1/4a
 II.6 (65 years)Palpitations+++2/1a
Family C
 IV.4 (23 years)Syncope+ (V2–V6)+++ (RV + LV)VT/VF2/3a
 III.5 (52 years)+++ (LV > RV)0/3
 III.1 (65 years)None++++0/4a
 IV.1 (38 years)Atypical Chest pain+++0/3b
 IV.2 (36 years)Palpitations++1/1b
 IV.3 (24 years)Palpitations+0/1
Family D
 III.3 (38 years)++ (Inf leads V3–V6)++ (RV + LV)+NSVT2/3a
 II.2 (64 years)++2/0a
Family E
 IV.14 (27 years)++1/1b
 III.16 (46 years)Palpitations++c+2/1a
 IV.20 (19 years)+++1/2a
 II.5 (80 years)SOB+1/0
Family F
 III.6 (49 years)Syncope+ (V1–V3)+++1/3a
 III.5 (52 years)Palpitations++ (V1–V3)+1/2a
 IV.4 (15 years)++1/1
 IV.5 (13 years)Palpitations++1/1
Family G
 Proband's father (48 years)+++1/2a
Family H
 Proband (46 years)Syncope++++NSVT1/3a
Family I
 Proband's son (35 years)++++2/2a
  • LV indicates left ventricle; NSVT, non-sustained ventricular tachycardia, usually detected on ambulatory monitoring or exercise testing (3 beats—30 sec duration at ≥ 120/min); PVCs, Premature Ventricular Complexes as recorded on ambulatory ECG monitoring (Holter); RV, right ventricle; SOB, shortness of breath.

  • aDenotes those who satisfy International Task Force Diagnostic Criteria.12

  • bDenotes those who satisfy Proposed Modified Diagnostic Criteria.13

  • cDenotes those who have > 200 PVCs in a 24 h period, as per Proposed Modified Diagnostic Criteria.13

Family D (Figure 1B). The proband (III.4) died suddenly, aged 26, and post-mortem findings were diagnostic of ARVC. His brother (III.3) had low voltage complexes and widespread T-wave inversion on ECG, RWMA, and fatty infiltration of both ventricles on CMR and NSVT on exercise testing. The proband's mother (II.2) showed left bundle branch block on ECG, but further specific clinical evaluation was not possible. Both were heterozygous for the D154E mutation in DSG2.

Family E (Figure 1C). The proband (III.11) died suddenly, aged 48, and his post-mortem was consistent with a diagnosis of ARVC. In this family, mutation V158G was found in four individuals (II.5, III.16, IV.14, and IV.20). Two individuals fulfilled Task Force diagnostic criteria: III.16 (positive findings on ECG, contrast-enhanced echo, and CMR) and IV.20 (findings on signal-averaged ECG and imaging). The proband's daughter (IV.14) only fulfils proposed modified diagnostic criteria whilst the proband's father (II.5) has changes confined to the LV and therefore does not fulfil ARVC diagnostic criteria. In particular, his cardiac imaging demonstrated an apparently normal right ventricle but a mildly dilated left ventricle (118% of predicted for body surface area), with RWMA (akinesia of anterior septum and apex with hypokinesia of mid-apical inferior and anterior walls), and globally mild-to-moderate reduction of systolic function (EF 40–45%).

Family F (Figure 1C). The proband (III.6) presented with recurrent syncope aged 45. Diagnosis was based on ECG (partial right bundle branch block, T-wave inversion in V1–V3, and prominent epsilon waves) and cardiac imaging (global enlargement of RV with impaired systolic function). Recurrent VT of left bundle branch block morphology was documented and an ICD was implanted. Genetic screening of the proband's children (IV.6, IV.7, and IV.8) has been deferred for the present in view of their young age. The proband's sister (III.5) who is a carrier of the V158G mutation showed depolarization and repolarization abnormalities on ECG. Her daughters (IV.4 and IV.5), aged 15 and 13, also carry this mutation and have ECG abnormalities but do not fulfil ARVC diagnostic criteria.

Family G. The proband presented with sudden cardiac death aged 17 years. Post-mortem findings suggested LV variant of ARVC as the underlying cause of death. His father, who is positive for the V920G mutation, has diagnostic findings on cardiac imaging (RWMA of the RV: hypokinesia of the anterior wall of the RV outflow tract and the apical free wall) and late potentials on signal-averaged ECG.

Family H. The proband presented aged 45 years with recurrent syncope. Diagnostic findings included localized QRS prolongation V1—V3, T-wave inversion, and mildly enlarged RV with RWMA (hypokinesia of anterior RV outflow tract and apical lateral wall). She has had a prophylactic ICD implanted.

Family I. The proband died suddenly aged 59 years. His post-mortem was consistent with a diagnosis of ARVC. His asymptomatic son showed positive findings on ECG, signal-averaged ECG, and echo.

Other family members in Families G, H, and I were either unavailable for or declined clinical and genetic screening.

In total, six patients received an ICD, three for primary prophylaxis, and three following haemodynamically compromising ventricular arrhythmia. Of those who received an ICD for secondary prophylaxis, two have had at least one appropriate discharge over a mean of 9.3 years follow-up. Two are being treated with high-dose Sotalol and the third with Amiodarone. Of the three patients with ICD implanted for primary prophylaxis, none has received ICD therapy during a mean of 17 months follow-up. One patient is being treated with Sotalol, another with Bisoprolol. The third patient who had high volume ventricular ectopy and recurrent brief NSVT arising from the RV outflow tract had radiofrequency ablation performed with symptomatic and objective success and is currently not receiving anti-arrhythmic therapy.

Clinical data of all individuals carrying a mutation in DSG2 are summarized in Table 2. Morphological abnormalities were detected in 66% of DSG2 mutation carriers, LV involvement (enlargement and/or impaired function) in 25%, and classical precordial T-wave inversion only in 26%. Sustained ventricular arrhythmia was present in 8% and a family history of sudden death (SD)/aborted SD in six families (66%).

The mean age at diagnosis for probands in the DSG2 group (n = 9) was 32.6 (range 14–59 years) and in the group with no gene identified (n = 77) was 42.2 (range 8–68 years).


In this study we describe eight novel mutations in the DSG2 gene in families with ARVC.

All mutations are predicted to disrupt functionally important parts of DSG2 (Table 1). The C591X mutation in Family A is located in exon 12 of DSG2, which corresponds to the extracellular anchor domain of DSG2. Desmosome assembly is thought to be dependent on the presence of cadherin/plakoglobin complexes; cells lacking E-cadherin/plakoglobin complexes are unable to form desmosomes.15 The two base-pair deletion is predicted to cause truncation of the DSG2 molecule, with loss of the transmembrane and cytoplasmic components, where binding sites for plakoglobin (ICS domain) and plakophilin are located.8,16

In Family B, the 829_840delCTTGAAGGGATG mutation deletes the first 12 bases in exon 8 and would disrupt the splice acceptor site of this exon. This sequence change may cause skipping of exon 8 or alternatively activate a cryptic splice acceptor site in exon 8 or intron 8. Indeed, use of splice prediction computer programmes showed that the splice acceptor site for the mutant allele would be GTTTTGCAG//GTTG (wild-type score 0.76, mutant score 0.97, Neural Network)17 resulting in deletion of four amino acid residues (LEGM) in EC3. However, as heart/skin biopsies from an affected individual were not available for further analysis, this prediction remains speculative.

The 3G > C mutation seen in Family C is predicted to affect the initiation of translation of the DSG2 protein. Start of translation of eukaryotic mRNA takes places via a scanning mechanism based on the first AUG codon and its flanking sequence.18 Studies of diseases caused by mutations destroying the normal start codon have shown that translation may initiate from alternative AUG codons (leading to longer or shorter mutant transcripts) or be entirely abolished.18 In the case of the 3G > C mutation it is unclear what the precise effect on the DSG2 protein would be. Unfortunately, cardiac material which could have provided an answer was not available from affected individuals in Family C.

The five missense mutations found in Families D–I affect highly conserved amino acid residues among DSG2 homologues (mouse, dog, chimpanzee, and human; data not shown). Mutations V56M and V392I disrupt conserved regions in EC1 and EC4, respectively. The extracellular domains of DSG2 and, in particular, EC1-2 are involved in the formation of heterodimers between desmogleins and desmocollins in a Ca2+ dependent manner.8,19 Such interactions are thought vital in achieving desmosomal adhesion.16 Desmogleins contain conserved sequence motifs in the extracellular domains which represent putative calcium binding sites (DXNDN and A/VXDXD).14 Their functional significance is underlined by the fact that D154 and V158 are conserved in dsg2 homologues as well as in human DSG1, DSG3, and DSG4. Finally, V920G is located within the conserved RUD which is believed to take part in forming β-strands.14 Further evidence to support disease-causation is provided by the normal clinical evaluations in 38 individuals in Families A–F who were either confirmed to have the wild-type sequence, or their relevant parent was tested and found to be wild-type. No family member evaluated who was gene negative fulfilled Task Force criteria for ARVC.

Although DSG2 is expressed in epidermis, none of the individuals carrying a DSG2 mutation had clinical evidence of hair or skin abnormalities. This agrees with the findings in recent studies, where patients with DSG2 mutations had no such abnormalities.9,10 It is likely that the lack of cutaneous phenotype in DSG2 mutations carriers may be due to functional substitution of DSG2 by other desmoglein isoforms expressed in the skin.

The penetrance of DSG2 mutations in the families described in this study is relatively high. Using the Task Force criteria12 as the definition of complete penetrance, desmoglein mutations are 58% penetrant. Using the proposed modified criteria13 an additional four subjects could be described as affected, raising the penetrance to 75%, which is comparable with our experience in families with plakophilin-2 mutations.11 ARVC is a progressive cardiac disorder and younger individuals with few or no clinical features may develop disease later in life. Dividing gene positive individuals into age groups (20–40 and >40) shows higher penetrance in the older group (50 and 75% respectively, for Task Force criteria). However, even though this study presents the largest cohort of ARVC patients with DSG2 mutations to date, patient numbers are relatively low. Therefore, these findings will need to be confirmed in larger families with DSG2 mutations.

It could be argued that adherence to diagnostic criteria, which by definition exclude LV disease, is no longer defensible. In Family C, the father (III.5) of the severely affected proband has almost exclusively left-sided disease, both on imaging and in T-wave inversion on ECG. Similarly, the patriarch in Family E (II.5) has disease which clinically is restricted to the left ventricle, again with T-wave inversion in left precordial leads, ventricular enlargement, reduced systolic function, and prominent wall motion abnormalities. If we included those with isolated LV involvement, the penetrance would increase to 83%. Additionally, the youngest gene carriers in Family F (IV.4 and IV.5) have an epsilon wave on ECG. This fulfils neither Task Force criteria nor proposed modified criteria, but must be considered to be a likely manifestation of gene expression. The only gene positive patient with no evidence of ARVC on clinical investigation is the 79 year-old mother of the proband in Family A (II.2). Our clinical information on her is limited to a previous ECG, which does not show features of ARVC. However, further clinical investigation in her now will not be informative, as she has undergone intervention for complex coronary disease. This was complicated by RV perforation by a temporary pacing lead, which could have resulted from pre-existing structural abnormalities. Therefore, we can neither prove nor disprove gene penetrance in her case.

Our finding of LV involvement in 25% of the subjects with DSG2 mutations is quite similar to the findings in families with desmoplakin mutations,20 where 27% of all gene carriers had evidence of LV involvement, and considering only those subjects who fulfilled Task Force criteria, 43% had LV involvement. This is quite a high percentage considering that the Task Force criteria require that no more than mild LV disease be considered compatible with a diagnosis of ARVC.12 As the identification of a mutation in a known gene must be considered a gold standard in the diagnosis of ARVC, the clinical diagnostic criteria should be amended to reflect the documented high prevalence of biventricular or LV predominant disease, as found in some of our DSG2 families.

Heart failure symptoms were not a prominent feature in any of our patients, despite one having a calculated LV ejection fraction of 15% (IV.4, Family C) and another of 25% (III.4, Family B). This may be a function of the duration of the condition as both these men presented at a young age (14 and 16 years, respectively) and possibly have a distorted concept of normal functional capacity for their age. Objective measurement with peak VO2 measurement is difficult to interpret in one (peak of 18 mL/min/kg but with a body mass index of 40) and has been repeatedly declined by the other. It is possible that the lack of heart failure symptoms is mutation-related, but studies of larger numbers of patients with DSG2 mutations would be required to assess this.

Family history of SD and aborted SD was present in six families (66%). This is similar to the findings of a previous study in which a family history of SD was reported in a total of four out of eight probands with DSG2 mutations.9 The occurrence of sustained ventricular arrhythmia was similar in the group with DSG2 mutations and those with no identified mutations (data not shown). As LV involvement is one of the most consistent negative prognostic indicators in ARVC,21,22 the occurrence of LV involvement in similar proportions in both groups may explain this. We detected LV involvement is approximately half of the probands without a desmosomal gene identified, which is perhaps unusually high. This may reflect our current practice of interpreting the Task Force criteria to include LV variants of disease, rather than adhering to them strictly as published. This may increase the risk of including phenocopies into our cohort. A comparison with individuals affected with each of the other desmosomal genes would be of interest.

ECG generally provides evidence of disease expression in most patients with ARVC. We found characteristic T-wave inversion in right precordial leads, which fulfils Task Force criteria in only one-quarter of our patients with desmoglein mutations. The original concept of diagnosing ARVC on the basis of isolated RV disease is no longer appropriate given the well-established prevalence of LV involvement. In patients with a desmoglein mutation, we found T-wave inversion in inferior leads in 13%, and in left precordial leads in 26%, and overall 39% had an abnormal ECG with T-wave inversion in at least one distribution. This reflects the heterogeneity of disease expression in ARVC, even within families carrying the same mutation. The finding of RV wall motion abnormalities in our youngest subject (IV.2, Family A), aged 11, identifies another limitation of the current criteria. By definition, the criteria exclude consideration of T-wave inversion in right precordial leads to be an indication of disease expression in those less than 12 years. This was probably appropriate at a time when disease expression was considered not to occur before adolescence. Here, we have evidence of gene expression by the age of 11, and therefore a benchmark for ECG interpretation in these pre-teen years would be an advantage. These findings underscore the need for modification of the Task Force criteria.


We describe novel mutations in the DSG2 gene in six families and three individuals with ARVC. Our study provides further evidence for a role for DSG2 in the pathogenesis of ARVC and strengthens the view that ARVC is a disease of the desmosome. It also adds to the evidence that ARVC is neither exclusively an RV disease nor a disease confined to adolescence and adulthood and our diagnostic tools should reflect this.


This work was supported by the British Heart Foundation and the EC 5th Framework Program (ARVC/D project, QLG1-CT-2000-01091). We thank the patients and family members for taking part in this study.

Conflict of interest: none declared.


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