Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy

A H Christensen; M Benn; H Bundgaard; A Tybjaerg-Hansen; Stig Haunsø; J H Svendsen

doi:10.1136/jmg.2010.077891

Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy

A H Christensen, M Benn, H Bundgaard, A Tybjaerg-Hansen, Stig Haunsø, J H Svendsen

47 Citations (Scopus)

Abstract

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a lethal condition characterised by ventricular tachyarrhythmias, right and/ or left ventricular involvement and fibrofatty infiltrations in the myocardium. The disease has been associated with mutations in genes encoding desmosomal proteins. Objective: To thoroughly evaluate an ARVC cohort for desmosomal mutations and large genomic rearrangements and characterise the phenotype associated with double-mutation carrier status. Methods: 65 unrelated patients (55 fulfilling current criteria and 10 borderline cases) were screened for mutations in all known desmosome genes (desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP) and plakophilin-2 (PKP2)) and TGFb3. Presence of genomic rearrangements was assessed by multiplex ligation-dependent probe amplification. Results: The screening identified 19 different mutations: two mutations in DSG2, four in DSC2, two in DSP (one heterozygous and one homozygous), four in JUP (one patient with compound heterozygous) and seven in PKP2. No genomic rearrangements or mutations in TGFb3 were identified. Ten of the mutations were novel. Seven families carried more than one mutation. Clinical evaluation of these families showed a variable phenotype associated with the double-mutation carrier status. The homozygous desmoplakin mutation (DSP p.G2056R+p. G2056R) carrier came from a consanguineous Danish family and had left ventricular involvement, palmar keratoderma and curly hair consistent with a Carvajal-like syndrome. Conclusions: 33% of patients in this Danish cohort with ARVC carried desmosomal mutations with a surprisingly wide mutation spectrum. A substantial proportion of patients carried more than one mutation. Our study supports comprehensive desmosomal mutation screening beyond the first encountered mutation, whereas routine screening for genomic rearrangements does not seem indicated.

Original language	English
Journal	Journal of Medical Genetics
Volume	47
Issue number	11
Pages (from-to)	736-44
Number of pages	9
ISSN	1468-6244
DOIs	https://doi.org/10.1136/jmg.2010.077891
Publication status	Published - Nov 2010

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10.1136/jmg.2010.077891

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title = "Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy",

abstract = "Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a lethal condition characterised by ventricular tachyarrhythmias, right and/ or left ventricular involvement and fibrofatty infiltrations in the myocardium. The disease has been associated with mutations in genes encoding desmosomal proteins. Objective: To thoroughly evaluate an ARVC cohort for desmosomal mutations and large genomic rearrangements and characterise the phenotype associated with double-mutation carrier status. Methods: 65 unrelated patients (55 fulfilling current criteria and 10 borderline cases) were screened for mutations in all known desmosome genes (desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP) and plakophilin-2 (PKP2)) and TGFb3. Presence of genomic rearrangements was assessed by multiplex ligation-dependent probe amplification. Results: The screening identified 19 different mutations: two mutations in DSG2, four in DSC2, two in DSP (one heterozygous and one homozygous), four in JUP (one patient with compound heterozygous) and seven in PKP2. No genomic rearrangements or mutations in TGFb3 were identified. Ten of the mutations were novel. Seven families carried more than one mutation. Clinical evaluation of these families showed a variable phenotype associated with the double-mutation carrier status. The homozygous desmoplakin mutation (DSP p.G2056R+p. G2056R) carrier came from a consanguineous Danish family and had left ventricular involvement, palmar keratoderma and curly hair consistent with a Carvajal-like syndrome. Conclusions: 33% of patients in this Danish cohort with ARVC carried desmosomal mutations with a surprisingly wide mutation spectrum. A substantial proportion of patients carried more than one mutation. Our study supports comprehensive desmosomal mutation screening beyond the first encountered mutation, whereas routine screening for genomic rearrangements does not seem indicated.",

author = "Christensen, {A H} and M Benn and H Bundgaard and A Tybjaerg-Hansen and Stig Hauns{\o} and Svendsen, {J H}",

year = "2010",

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doi = "10.1136/jmg.2010.077891",

language = "English",

volume = "47",

pages = "736--44",

journal = "Journal of Medical Genetics",

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publisher = "B M J Group",

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TY - JOUR

T1 - Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy

AU - Christensen, A H

AU - Benn, M

AU - Bundgaard, H

AU - Tybjaerg-Hansen, A

AU - Haunsø, Stig

AU - Svendsen, J H

PY - 2010/11

Y1 - 2010/11

N2 - Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a lethal condition characterised by ventricular tachyarrhythmias, right and/ or left ventricular involvement and fibrofatty infiltrations in the myocardium. The disease has been associated with mutations in genes encoding desmosomal proteins. Objective: To thoroughly evaluate an ARVC cohort for desmosomal mutations and large genomic rearrangements and characterise the phenotype associated with double-mutation carrier status. Methods: 65 unrelated patients (55 fulfilling current criteria and 10 borderline cases) were screened for mutations in all known desmosome genes (desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP) and plakophilin-2 (PKP2)) and TGFb3. Presence of genomic rearrangements was assessed by multiplex ligation-dependent probe amplification. Results: The screening identified 19 different mutations: two mutations in DSG2, four in DSC2, two in DSP (one heterozygous and one homozygous), four in JUP (one patient with compound heterozygous) and seven in PKP2. No genomic rearrangements or mutations in TGFb3 were identified. Ten of the mutations were novel. Seven families carried more than one mutation. Clinical evaluation of these families showed a variable phenotype associated with the double-mutation carrier status. The homozygous desmoplakin mutation (DSP p.G2056R+p. G2056R) carrier came from a consanguineous Danish family and had left ventricular involvement, palmar keratoderma and curly hair consistent with a Carvajal-like syndrome. Conclusions: 33% of patients in this Danish cohort with ARVC carried desmosomal mutations with a surprisingly wide mutation spectrum. A substantial proportion of patients carried more than one mutation. Our study supports comprehensive desmosomal mutation screening beyond the first encountered mutation, whereas routine screening for genomic rearrangements does not seem indicated.

AB - Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a lethal condition characterised by ventricular tachyarrhythmias, right and/ or left ventricular involvement and fibrofatty infiltrations in the myocardium. The disease has been associated with mutations in genes encoding desmosomal proteins. Objective: To thoroughly evaluate an ARVC cohort for desmosomal mutations and large genomic rearrangements and characterise the phenotype associated with double-mutation carrier status. Methods: 65 unrelated patients (55 fulfilling current criteria and 10 borderline cases) were screened for mutations in all known desmosome genes (desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP) and plakophilin-2 (PKP2)) and TGFb3. Presence of genomic rearrangements was assessed by multiplex ligation-dependent probe amplification. Results: The screening identified 19 different mutations: two mutations in DSG2, four in DSC2, two in DSP (one heterozygous and one homozygous), four in JUP (one patient with compound heterozygous) and seven in PKP2. No genomic rearrangements or mutations in TGFb3 were identified. Ten of the mutations were novel. Seven families carried more than one mutation. Clinical evaluation of these families showed a variable phenotype associated with the double-mutation carrier status. The homozygous desmoplakin mutation (DSP p.G2056R+p. G2056R) carrier came from a consanguineous Danish family and had left ventricular involvement, palmar keratoderma and curly hair consistent with a Carvajal-like syndrome. Conclusions: 33% of patients in this Danish cohort with ARVC carried desmosomal mutations with a surprisingly wide mutation spectrum. A substantial proportion of patients carried more than one mutation. Our study supports comprehensive desmosomal mutation screening beyond the first encountered mutation, whereas routine screening for genomic rearrangements does not seem indicated.

U2 - 10.1136/jmg.2010.077891

DO - 10.1136/jmg.2010.077891

M3 - Journal article

C2 - 20864495

SN - 0022-2593

VL - 47

SP - 736

EP - 744

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 11

ER -

Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy

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