News archive
October 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
October 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.
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October 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).
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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).
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August 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.
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July 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.
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July 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.
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June 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.
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June 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.
May 24, 2011.
Circulation published two articles online on comprehensive DNA analysis in ARVD/C patients as well as their family members:
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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.
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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.
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March 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.
March 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
.
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March 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.
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February 9, 2011.
As a part of a series on recurrent and founder mutations in the Netherlands, we described 12 ARVC families in the Netherlands, all carrying the R79X founder mutation in PKP2, in the Netherlands Heart Journal.
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January 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.
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January 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.
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October 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.
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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.
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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.
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August 30, 2010.
Multiple presentations from the 2010 ESC Congress in Stockholm were added to the database:
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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
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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
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O'Mahony et al. presented their recently added data on desmosomal mutations in DCM patients.
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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.
August 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.
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August 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
June 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.
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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).
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March 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.
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February 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.
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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
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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
October 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.
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October 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.
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October 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.
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August 31, 2009.
Krahn et al. found mutations in two ARVD/C patients who survived cardiac arrest, including a novel one in DSP.
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July 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.
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July 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
July 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.
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June 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.
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May 15, 2009.
Another article describing 5 novel PKP2 variants found in Chinese ARVD/C patients by Qiu et al. was added to the database.
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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".
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March 13, 2009.
PKP2 variants found in Chinese ARVD/C patients by Wu et al. were added to the database.
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March 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.
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March 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.
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February 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.
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.
October 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.