Impact of Laboratory Molecular Diagnosis on Contemporary Diagnostic Criteria for Genetically Transmitted Cardiovascular Diseases: Hypertrophic Cardiomyopathy, Long-QT Syndrome, and Marfan Syndrome

Maron, Barry J.; Moller, James H.; Seidman, Christine E.; Vincent, G; Dietz, Harry C.; Moss, Arthur J.; Towbin, Jeffrey A.; Sondheimer, Henry M.; Pyeritz, Reed E.; McGee, Glenn; Epstein, Andrew E.

doi:10.1161/01.cir.98.14.1460

Cited by 125 publications

(83 citation statements)

References 151 publications

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“…Therefore, young people with negligible manifestations of disease, who may harbor only preclinical (ie, molecular) evidence of a particular disease-causing mutation predisposing to GCVD, are excluded. 1,2,5,8,14,16,26,44,45 Furthermore, at present, it is unresolved as to whether genotype-positive/phenotype-negative individuals warrant any restrictions from either recreational or competitive sports.…”

Section: Objectives Of the Panelmentioning

confidence: 99%

“…Mutation analysis for the purpose of risk stratification of sudden death, although prominently portrayed in the subspecialty literature, [1][2][3][4][7][8][9][10][11][12]16,[55][56][57][58][59][60][61][62][63][64][65][66][67] has limited practical impact on the present considerations. First, the diagnostic strategy of DNA analysis is time consuming, expensive, and limited to a small number of highly specialized research-oriented laboratories 1,2,8,64 -67 and thus is not yet routinely available to the practicing clinician for the purpose of patient management and formulation of exercise recommendations.…”

Section: Role Of Genetic Analysismentioning

confidence: 99%

“…For example, in LQTS, swimming, abrupt loud noises (such as from a race starter's pistol), and diving have been implicated as triggers for sudden death, particularly with certain mutant genes (ie, KCNQ1 [or LQT1] for swimming and KCNH2/HERG [or LQT2] for auditory triggers). 1,3,4,8,[55][56][57][58][59][60][61] However, such laboratory-based molecular information is unlikely to be available to clinicians prospectively making exercise recommendations. Patients with rare conditions such as CPVT, 13,15 in which many forms of exercise are associated with catecholamine release that triggers ventricular tachycardia, should be cautioned against virtually all forms of vigorous physical activity.…”

Section: Patient Recommendationsmentioning

confidence: 99%

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Recommendations for Physical Activity and Recreational Sports Participation for Young Patients With Genetic Cardiovascular Diseases

Maron¹,

Chaitman²,

Ackerman³

et al. 2004

Circulation

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503

294

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Abstract-A group of relatively uncommon but important genetic cardiovascular diseases (GCVDs) are associated with increased risk for sudden cardiac death during exercise, including hypertrophic cardiomyopathy, long-QT syndrome, Marfan syndrome, and arrhythmogenic right ventricular cardiomyopathy. These conditions, characterized by diverse phenotypic expression and genetic substrates, account for a substantial proportion of unexpected and usually arrhythmia-based fatal events during adolescence and young adulthood. Guidelines are in place governing eligibility and disqualification criteria for competitive athletes with these GCVDs (eg, Bethesda Conference No. 26 and its update as Bethesda Conference No. 36 in 2005). However, similar systematic recommendations for the much larger population of patients with GCVD who are not trained athletes, but nevertheless wish to participate in any of a variety of recreational physical activities and sports, have not been available. The practicing clinician is frequently confronted with the dilemma of designing noncompetitive exercise programs for athletes with GCVD after disqualification from competition, as well as for those patients with such conditions who do not aspire to organized sports. Indeed, many asymptomatic (or mildly symptomatic) patients with GCVD desire a physically active lifestyle with participation in recreational and leisure-time activities to take advantage of the many documented benefits of exercise. However, to date, no reference document has been available for ascertaining which types of physical activity could be regarded as either prudent or inadvisable in these subgroups of patients. Therefore, given this clear and present need, this American Heart Association consensus document was constituted, based largely on the experience and insights of the expert panel, to offer recommendations governing recreational exercise for patients with known GCVDs.

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Section: Objectives Of the Panelmentioning

confidence: 99%

Section: Role Of Genetic Analysismentioning

confidence: 99%

Section: Patient Recommendationsmentioning

confidence: 99%

See 1 more Smart Citation

Recommendations for Physical Activity and Recreational Sports Participation for Young Patients With Genetic Cardiovascular Diseases

Maron¹,

Chaitman²,

Ackerman³

et al. 2004

Circulation

Self Cite

503

294

View full text Add to dashboard Cite

show abstract

“…individuals with a compatible family history and clinical presentation consistent with the diagnosis of familial LQTS. 13,14 The expected cost-effectiveness of confirmatory genetic testing involving either first-degree relatives (offspring, siblings, 4 parents) or more distant relatives was not included in this analysis. We modeled current practice by a heart rhythm specialist who is evaluating a putative proband or index case rather than potentially affected family members.…”

Section: Populationmentioning

confidence: 99%

Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases

et al. 2005

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“…So far, the diagnosis of MFS has been made clinically. Recently, however, the inclusion of FBN1 mutations as a diagnostic criterion has been proposed [De Paepe et al, 1996;Maron et al, 1998]. Molecular analysis of FBN1 would be valuable for presymptomatic diagnosis and genetic counseling as well as for a better understanding of the phenotypic variability of MFS and related disorders .…”

Section: Mutations In the Human Fibrillin 1 Gene (Fbn1) Cause The Marmentioning

confidence: 99%

Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in theFBN1gene

et al. 2002

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Mutations in the human fibrillin 1 gene (FBN1) cause the Marfan syndrome (MFS), an autosomal dominant connective tissue disorder. Knowledge about FBN1 mutations is important for early diagnosis, management, and genetic counseling. However, mutation detection in FBN1 is a challenge because the gene is very large in size (~200 kb) and the ~350 mutations detected so far are scattered over 65 exons. Conventional methods for large-scale detection of mutations are expensive, technically demanding, or time consuming. Recently, a high-capacity low-cost mutation detection method was introduced based on denaturing high-performance liquid chromatography (DHPLC). To assess the sensitivity and specificity of this method, we blindly screened 64 DNA samples of known FBN1 genotype exon-by-exon using exon-specific DHPLC conditions. Analysis of 682 PCR amplicons correctly identified 62 out of 64 known sequence variants. In three MFS patients of unknown FBN1 genotype, we detected two mutations and eight polymorphisms. Overall, 20 mutations and two polymorphisms are described here for the first time. Our results demonstrate 1) that DHPLC is a highly sensitive (8999%, P = 0.05) method for FBN1 mutation detection; but 2) that chromatograms with moderate and weak pattern abnormalities also show false positive signals (in all 4559%, P = 0.05); 3) that the difference in the chromatograms of heterozygous and homozygous amplicons is mostly independent of the type of sequence change; and 4) that DHPLC column conditions, additional base changes, and the amounts of injected PCR products influence significantly the shape of chromatograms. A strategy for FBN1 mutation screening is discussed. [Dietz et al., 1991]. The autosomal dominant MFS affects ∼1:10,000 individuals, without gender or ethnic predisposition [Gray et al., 1994;Pyeritz, 2000]. The disease is characterized by skeletal, ocular, and cardiovascular manifestations and exhibits a broad range of severity [Pyeritz, 2000]. Aortic aneurysms and dissections are the life-threatening events that can be prevented by timely cardiovascular surgery [Finkbohner et al., 1995]. So far, the diagnosis of MFS has been made clinically. Recently, however, the inclusion of FBN1 mutations as a diagnostic criterion has been proposed [De Paepe et al., 1996;Maron et al., 1998]. Molecular analysis of FBN1 would be valuable for presymptomatic diagnosis and genetic counseling as well as for a better understanding of the phenotypic variability of MFS and related disorders .The FBN1 gene, located on chromosome 15q21, is about 200 kb in size and contains 65 exons encoding 2,871 amino acids and four additional alternatively spliced exons at the 5′ end of the gene [Kainulainen et al., 1990;Pereira et al., 1993;Biery et al., 1999]. The ∼350 FBN1 mutations reported so far (Marfan Database; personal communication with G. Beroud and C. Boileau) are scattered over all 65 exons and are largely unique to each affected family (http:// archive.uwcm.ac.uk/uwcm/mg/search/127115. html) . Furthermore, clear genotypephenotype ...

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Impact of Laboratory Molecular Diagnosis on Contemporary Diagnostic Criteria for Genetically Transmitted Cardiovascular Diseases: Hypertrophic Cardiomyopathy, Long-QT Syndrome, and Marfan Syndrome

Cited by 125 publications

References 151 publications

Recommendations for Physical Activity and Recreational Sports Participation for Young Patients With Genetic Cardiovascular Diseases

Recommendations for Physical Activity and Recreational Sports Participation for Young Patients With Genetic Cardiovascular Diseases

Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases

Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in theFBN1gene

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