News archive

februari 10, 2015.

Our paper on the 2014 update of www.arvcdatabase.info is published online in Human Mutation! See Lazzarini et al.

februari 1, 2015.

Since the launch of www.arvcdatabase.info in 2008, the website had over 230,000  page loads and over 21,000 returning visitors.
Currently, the database contains 1431 unique variants, reported in 171 papers and abstracts.

mei 22, 2014.

We have added two papers to the database, one on functional studies in DES mutations (Brodehl et al.) and one on a novel recessive inherited DSC2 mutation in ARVC (Al-Sabeq et al.):

- Brodehl et al. Journal of Biological Chemistry 2012.See article details
- Al-Sabeq et al. Canadian Journal of Cardiology 2014.See article details

april 17, 2014.

Pugh et al. reported the results of gene panel testing in a large cohort of 766 DCM patients. Mutations in DSP were identified in 2.4% of patients. Those variants that were identified in genes previously related to ARVC are added to the database.
See article details

maart 11, 2014.

Cerrone et al. published results their PKP2 sequencing in a cohort of 200 proven Brugada syndrome patients without signs of arrhythmogenic cardiomyopathy and no mutations in BrS-related genes. Five missense variants were identified. These mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2. Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of the five Brugada syndrome-related PKP2 mutants.
See article details

maart 1, 2014.

We are working on an update of www.arvcdatabase.info. Therefore, until recently new papers and mutations have not been added to the database. We have now added several papers and are working on the remaining papers from 2013 and 2014.
We have added the following papers to the database:

- Ostrowska Dahlgren et al. Journal of Interventional Cardiac Electrophysiology 2012.See article details
- Larsen et al. Forensic Science International 2012.See article details
- Quarta et al. European Heart Journal 2012.See article details
- Nakajima et al. Circulation Journal 2012.See article details
- Rajkumar et al. BMC medical genetics 2012.See article details
- Kirchner et al. Circulation Cardiovascular Genetics 2012.See article details
- van der Zwaag et al. European Journal of Heart Failure 2012.See article details
- te Riele et al. JACC Cardiovascular Imaging 2012.See article details
- Keller et al. Swiss Medical Weekly 2012.See article details
- Gaertner et al. PLoS One 2012.See article details
- van der Smagt et al. Cardiology 2012.See article details
- Anastasakis et al. Cardiology 2012.See article details
- Ma et al. European Heart Journal 2013.See article details
- Noorman et al. Heart Rhythm 2013.See article details
- van Hengel et al. European Heart Journal 2013.See article details
- Lorenzon et al. American Journal of Cardiology 2013.See article details
- Groeneweg et al. Heart Rhythm 2013.See article details
- Kim et al. Nature 2013.See article details
- Rasmussen et al. Human Mutation 2013.See article details
- Li Mura et al. European Journal of Human Genetics 2013.See article details
- van der Zwaag et al. Netherlands Heart Journal 2013.See article details
- Lahtinen et al. Annals of Medicine 2013.See article details
- Baskin et al. Human Genetics 2013.See article details
- Gerull et al. Circulation Cardiovascular Genetics 2013.See article details
- Campuzano et al. European Journal of Medical Genetics 2013.See article details
- Kumar et al. Heart Rhythm 2013.See article details
- Ohno et al. Circulation Journal 2013.See article details
- Saguner et al. Circulation 2013.See article details
- Rigato et al. Circulation Cardiovascular Genetics 2013.See article details
- Vite et al. PLoS One 2013.See article details
- Bao et al. Circulation Cardiovascular Genetics 2013.See article details
- Brodehl et al. Circulation Cardiovascular Genetics 2013.See article details
- Caspi et al. Circulation Cardiovascular Genetics 2013.See article details

april 13, 2012.

Exome sequencing identified a DES mutation in a family with ARVC, in which a previous study by Melberg et al. had demonstrated linkage to chromosome 10q22.3. Hedberg et al. identified the mutation in seven out of ten family members that had been classified as affected in the previuos study.
See mutation details

november 14, 2011.

Aström-Aneq et al. identified an unpublished nonsense variant in PKP2, found in a three generation ARVC family. The phenotype was characterized by arrhythmia at an early age in some individuals, with mild abnormalities on imaging.
See article details

oktober 26, 2011.

Zhang et al. sequenced PKP2 in DNA extracted from postmortem heart tissues of 25 patients who died from ARVC and 25 patients who died from sudden death with negative autopsy. PKP2 sequence variants were found in 12 patients, 6 in each group. Seven of these variants were considered pathogenic. 
See article details

oktober 21, 2011.

Taylor et al. identified 8 unique titin (TTN) variants in 7 ARVC families, including one large family with complete segregation. Sudden death was present in 5 of 7 families and 11 of 14 mutation carriers had conduction disease. 
See article details

oktober 1, 2011.

Since the launch of www.arvcdatabase.info, three years ago, the website had over 110,000  page loads and over 8,300 returning visitors. Currently, the database contains 830 unique variants, reported in 105 papers and abstracts.

september 1, 2011.

Williams et al. identified a novel homozygous deletion in DSP (c.5208_5209delAG; p.Gly1737Thrfsx7) in two boys with biventriculair cardiomyopathy; focal palmoplantar keratoderma and wooly hair (Carvajal syndrome).
See article details

september 1, 2011.

Palmisano et al. reported a father and son with ARVD/C. Both carried the previous reported splice mutation c.2489+1A>G in PKP2 and a novel unknown variant in DSC2 (c.327A>G; p.Ile109Met).
See article details

augustus 24, 2011.

Garcia-Pavia et al. sequenced 89 probands with end-stage DCM who underwent cardiac transplantation. None of these patients fulfilled the task force criteria for the diagnosis of ARVD/C. Pathogenic mutations were found in 12 patients (13%). These include mutations that were previously classified in this database as a variant of unknown effect which co-segregated with DCM on family screening.
See article details

juli 7, 2011.

Al-Jasser et al. studied the plakin domain of desmoplakin (DSP), providing structural and mechanistic insights, and provides a basis for understanding the critical role of desmoplakin in desmosome function. This is illustrated by studies into the mutations K470E and R808C in DSP.
The plakin domain (residues 180-1022) contains six spectrin repeats; these spectrin repeats are listed under 'domain' at the variant details pages.

See article details

juli 5, 2011.

A paper by Bauce et al. was published online in Heart Rhythm. The aim of the study was to describe the ARVC phenotype as its initial clinical manifestation, in a pediatric population (<18yrs), with (previously described) desmosomal gene mutations. A diagnosis of ARVC was achieved in 40% of cases.
See article details

juni 11, 2011.

A paper by Erken et al. was published online in the British Journal of Dermatology. They identified a homozyogous mutation in JUP, resulting in ARVD/C associated with alopecia and palmoplantar keratoderma, expanding the clinical spectrum of disorders associated with mutations affecting dsmosomal proteins.
See article details

juni 7, 2011.

Kapplinger et al. sequenced 93 probands with ARVD/C from the Netherlands and 427 ostensibly healthy controls from diifferent ethnicities. The overall yield of mutations was 58% among ARVC cases (details can be found in the publication by Cox et al.) versus 16% in controls. They concluded that radical mutations are high-probability ARVC associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation.
See article details for an overview of all variants found in 1/427 controls.

mei 24, 2011.

Circulation published two articles online on comprehensive DNA analysis in ARVD/C patients as well as their family members:
  • Cox et al. described a cohort of 149 ARVD/C index patients, and 302 relatives. Pathogenic mutations, mainly truncating PKP2 mutations, were identified in 58% of Dutch index patients, and even in 90% of familial cases. Multiplex ligation-dependent probe amplification (MLPA) analysis identified three large deletions in PKP2.
    See article details
  • Quarta et al. studied 100 families assessed for ARVD/C.A definite or probable causal mutation was found in 58% of families. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease. 
    See article details

april 20, 2011.

The ARVC Calculator is designed for physicians to help determine if a patient meets the 2010 modified Task Force Criteria for ARVC.

april 19, 2011.

Navarro-Manchón et al. described a Spanish family with left dominant arrythmogenic cardiomyopathy (LDAC), caused by a novel nonsense mutation (Q1866X) in DSP.
See article details

maart 24, 2011.

The arvcdatabase is now on twitter! Follow us via twitter.com/arvcdatabase and stay updated. 
Follow arvcdatabase on Twitter

maart 23, 2011.

Christenen at al. screened three novel candidate genes for ARVC: the genes encoding b-catenin (CTNNB1), a-T-catenin (CTNNA3), and PERP (PERP), all important structuiral proteins at the intercalated disc. They did not identify any disease-causing mutations.

maart 9, 2011.

Lahtinen et al.  published their results on desmosomal mutations in a Finnish ARVC cohort. Furthermore, they analyzed the identified mutations in a population cohort of 6,334 individuals. 0.5% of the Finnish population was found to carry a desmosomal mutation that may predispose to ARVC .
See article details

maart 3, 2011.

A paper by Gandjbakhch et al. was published online in Heart. It addressed the specific case of the pathogenicity of mutations in PKP2 exon 6, which are specific for the long isoform PKP2b. They observed that the short isoform PKP2a is the unique proteic isoform expressed in heart, suggesting that variants located in PKP2 exon 6 are rare polymorphisms that the systematic molecular screening of PKP2 exon 6 is useless in ARVC and could be abandoned.
See article details

februari 9, 2011.

As a part of a series on recurrent and founder mutations in the Netherlandswe described 12 ARVC families in the Netherlands, all carrying the R79X founder mutation in PKP2, in the Netherlands Heart Journal.
See article details

januari 12, 2011.

In addition to the recently published mutations in DSC2, Gehmlich et al. identified another novel mutation in DSC2. They showed altered binding properties of the DSC2 mutant, which may contribute to changes in connexin43.
See article details

januari 12, 2011.

Previously, the work by Christensen et al, who analyzed the prevalence of TMEM43 mutations in a Danish cohort, was added to the database after the presenting at the ESC 2010. They identified variants in two families; one of unknown significance (c.705+7G>A), and a previously reported mutation (S358L). This work has now been published in Clinical Genetics.
See article details

januari 5, 2011.

Krishnamurthy et al. described the case of an 11-year-old girl with Carvajal disease, caused by a novel homozygous mutation (Q1301X) in DSP.
See article details

december 7, 2010.

Gehmlich et al. identified four novel mutations in DSC2. They functionally characterized two of the novel mutations (R203C and T275M) and the previously published variant (A897fsX900).
See article details

oktober 1, 2010.

Since the launch of www.arvcdatabase.info, two years ago, the website had 75,000 page loads and over 4,800 returning visitors. Currently, the database contains 714 unique variants, reported in 83 papers and abstracts.

september 23, 2010.

An extension of previous work by Christensen et al. describes the results of screening for desmosome gene mutations in a Danish cohort. The previous work was published in Cardiology in 2009. 
See article details

september 21, 2010.

Tan et al. studied whether individuals with earlier onset ARVD/C have more frequent desmosome gene mutations. The prevalence of mutations was similar in three different age groups.
See article details

september 9, 2010.

Klauke et al. genotyped a cohort of 22 ARVD/C patients. They found 16 variants, of which 8 are considered as pathogenic. Interestingly, they also screened for mutations in the intermediate filament gene Desmin (DES) and found a de novo missense mutation (N116S) in a patient who fulfilled the diagnostic criteria for the diagnosis of ARVD/C.
See article details

augustus 30, 2010.

Multiple presentations from the 2010 ESC Congress in Stockholm were added to the database:
  • Gandjbakhch et al. addressed the specific case of the pathogenicity of mutations in PKP2 exon 6, which are specific for the long isoform PKP2b. They observed that the short isoform PKP2a is the unique proteic isoform expressed in heart, suggesting that variants located in PKP2 exon 6 are rare polymorphisms that the systematic molecular screening of PKP2 exon 6 is useless in ARVC and could be abandoned.
    See article details
  • Christensen et al. analyzed the prevalence of TMEM43 mutations in a Danish cohort. They identified mutations in two families; one novel (c.705+7G>A) and one reported (S358L).
    See article details
  • O'Mahony et al. presented their recently added data on desmosomal mutations in DCM patients.
    See article details
  • Ortiz et al. analyzed the prevalence of mutations in an ARVD/C cohort from North West Spain. These results were also presented at the 2010 ESHG Conference in Gothenburg. See article details.

augustus 19, 2010.

Elliott et al. described the results of genetic testing in 100 unrelated patients with idiopathic dilated cardiomyopathy (DCM). 5 DCM patients were found to carry pathogenic desmosomal protein gene mutations; an additional 13 patients had sequence variants of uncertain pathogenic significance and were excluded from further comparative analysis. None of the 5 carriers of desmosomal mutations fulfilled current diagnostic criteria for ARVD/C, but 1 had fibrofatty change in the left ventricle at autopsy. They conclude that the study suggests that both clinical presentations can be caused by mutations in desmosomal protein genes.
See article details

augustus 17, 2010.

A manuscript on two novel mutations in the intracellular cadherin segment of DSG2 by Gehmlich et al. was added to the database. The results include functional work such as localization studies, binding assays and immuno-histochemistry. 
See
article details

juni 8, 2010.

La Gerche et al. described the results of genetic testing in athletes with complex arrhythmias of right ventricular origin and structural RV abnormalities to evaluate whether there is sufficient genetic overlap with ARVD/C to consider them the same or different entities. They found lower than expected rates of mutations in desmosomal genes, supporting the hypothesis that an ARVC-like phenotype may be acquired through intense exercise without an identifiable genetic predisposition.
See article details

april 26, 2010.

A report by Fressart et al. described the results of genetic testing in 135 ARVD/C probands from France and Switzerland. The results include the identification of 28 novel mutations. Genetic status consisting of multiple mutations was identified in 4% of patients and was associated with more frequent sudden death (p=0.047).
See article details

maart 8, 2010.

De Bortoli et al. described the results of genetic testing in 112 ARVD/C probands from Italy. The p.A897KfsX4 variation in DSC2 was also found in 6 (1.5%) out of 400 control chromosomes. The p.A897KfsX4 variation affects the last five amino acids of the DSC2a isoform but not of DSC2b, while in the heart DSC2b is more expressed than DSC2a, suggesting that relative deficiency of DSC2a might be compensated by isoform b. The authors concluded that the p.A897KfsX4 variation may be considered a rare variant, though possibly affecting phenotypic expression of concomitant ARVC/D mutations.
See article details

februari 5, 2010.

Xu et al. described the results of genetic testing in 198 ARVD/C probands from the U.S. and Italy. Their results include novel and previously reported mutations. They identified compound and digenic heterozygosity in many cases, suggesting that all desmosome-encoding genes should be screened in ARVD/C patients.
See article details

december 28, 2009.

Christensen et al. described the results of genetic testing of PKP2 in 53 ARVD/C patients from Denmark. Their results include several novel mutations and the finding of previously reported disease-causing mutations at a low frequency among healthy controls (D26N, S140F, and V587I), suggesting that these variants are disease modifying but not directly disease causing.
An extension of this work was published in J Med Genet in 2010 

See article details

november 3, 2009.

Barahona-Dussault et al. described the results of genetic testing in ARVD/C patients from a sincle center. Their results include several novel mutations and the analysis of polymorphisms in the 23 probands. 
See article details

oktober 19, 2009.

A manuscript on multiple mutations in desmosomal proteins encoding genes in ARVD/C by Bauce et al. was added to the database. These results were previously presented by Beffagna et al. at the 2008 congress of the European Society of Cardiology.
See
article details

oktober 5, 2009.

An abstract presented by De Bortoli et al. at the ESC Congress 2009 in Barcelona was added to the database. They screened for DSC2 mutations in 110 ARVD/C probands and evaluated possible mutations by immunostaining transfected murine cardiomyocytes and examining the expression pattern of the different DSC2 splice forms.
See article details

oktober 1, 2009.

Since the launch of www.arvcdatabase.info, one year ago, the website had over 35,000 page loads from 3,700 unique visitors. Currently, the database contains 575 unique variants.

september 10, 2009.

A report on the clinical characteristics and the spectrum of PKP2 mutations in patients from South Africa by Watkins et al. was added to the database. The results include 4 novel mutations.
See article details

augustus 31, 2009.

Krahn et al. found mutations in two ARVD/C patients who survived cardiac arrest, including a novel one in DSP.
See article details

juli 30, 2009.

Pilichou et al. studied the explanted heart of a proband carrying the DSG2 N266S mutation as well as transgenic mice with cardiac overexpression of the mouse equivalent of this mutation. They demonstrated for the first time that myocyte necrosis is the key initiator of myocardial injury, triggering progressive myocardial damage, including an inflammatory response and massive calcification within the myocardium, followed by injury repair with fibrous tissue replacement, and myocardial atrophy.
See article details

juli 28, 2009.

28 novel unpublished variants were added to the database. Currently, the database contains 136 unpublished variants, comprising about 24% of the total of 563 variants.
See details of unpublished variants

juli 13, 2009.

The results of a study by Huang et al. using transfected HEK cells to assess the effects of plakoglobin (JUP) mutations was added to the database.
Both the mutations S39_K40insS and G680fsX690 increased the speed of wound healing. However, the mutations have disparate effects on cell mechanical behaviour, suggesting complex biochemical roles for plakoglobin.
See article details

juni 9, 2009.

An article describing the database has been published online in Human Mutation:
A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy.
van der Zwaag PA, Jongbloed JD, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H, Hofstra RM, van Tintelen JP.
Hum Mutat. 2009;30(9):1278-83

juni 9, 2009.

The results of a comprehensive desmosome mutation analysis in a cohort of 100 North American Caucasians with ARVD/C by den Haan et al. was added to the database. The results include 8 novel mutations.
See article details

mei 15, 2009.

Another article describing 5 novel PKP2 variants found in Chinese ARVD/C patients by Qiu et al. was added to the database.
See article details

april 9, 2009.

Mutations listed in an article on cardiac magnetic resonance imaging (CMR) in family members of desmosomal mutation-carrying ARVD/C probands by Dalal et al. were added to the database. The authors describe a new morphlogic variant found on detailed CMR; a focal "crinkling" of the RV outflow tract and subtricuspid regions: the "accordion sign".
See article details

maart 13, 2009.

PKP2 variants found in Chinese ARVD/C patients by Wu et al. were added to the database.
See article details

maart 12, 2009.

Mutations listed in an article on immunohistochemical analysis of human myocardial samples as a diagnostic test for ARVD/C by Asimaki et al. were added to the database.
See article details

maart 9, 2009.

A case report by Tanaka et al. on compound heterozygous DSP mutations in a patient with early-onset cardiomyopathy and skin and hair abnormalities was added to the database.
See article details

februari 26, 2009.

The database was added to the Leiden Open Variants Database (LOVD) platform. For each variant/mutation a link to the corresponding LOVD-entry was added.
See www.lovd.nl/arvc for the full ARVD/C Genetic Variants Database at LOVD.

januari 21, 2009.

A short communication on the de novo desmoglein-2 mutation R49H, reported by Gandjbakhch et al. was added to the database.
See mutation details

december 28, 2008.

The observations of the cellular/molecular phenotype of two PKP2 mutations, reported by Joshi-Mukherjee et al. were added to the database.
See article details

december 19, 2008.

The mutations reported by Sen-Chowdhry et al. found in patients with left-dominant arrhythmogenic cardiomyopathy (LDAC) were added to the database.
See article details

december 15, 2008.

The results from in silico prediction methods for reported missense mutations have been added. For details see 'General Remarks'.

december 1, 2008.

Following the letter by Posch et al. and their paper mentioned below, the desmoglein-2 (DSG2) mutations V158G and V920G are now classified as polymorphisms. Because V56M might represent a susceptibility variation it is classified as an unclassified variant.

november 6, 2008.

The paper by Posch et al. concerning a missense variant in desmoglein-2 (DSG2) V56M, predisposing to dilated cardiomyopathy, including several polymorphisms in desmoglein-2 (DSG2) and desmocollin-2 (DSC2), was added.

oktober 12, 2008.

Following the letter from Milting and Klauke regarding the desmoglein-2 (DSG2) E713K mutation and the authors' response from Judge, the DSG2 E713K mutation is now classified as a polymorphism.

oktober 1, 2008.

First edition of arvcdatabase.info online