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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EDoes understanding the genotype\/phenotype of hypertrophic cardiomyopathy (HCM) influence management of the disease in relation to treatment, risk, and counseling? This article discusses the potential clinical value of molecular diagnosis in HCM. The most important contribution of mutation analysis is clarification of diagnosis rather than preclinical diagnosis (testing of asymptomatic carriers).\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Einflammatory disease genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EDoes understanding the genotype\/phenotype of hypertrophic cardiomyopathy (HCM) influence management of the disease in relation to treatment, risk, and counseling? William J. McKenna, MD, Heart Hospital, London, UK, addressed this question in the 2007 Rene Laennec Lecture on Clinical Cardiology. Prof. McKenna, whose research has focused primarily on the areas of cardiomyopathy and gene identification in inherited cardiovascular disease, discussed the potential clinical value of molecular diagnosis in HCM. He said that the most important contribution of mutation analysis is clarification of diagnosis rather than preclinical diagnosis (testing of asymptomatic carriers).\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EDiagnosis of HCM\u003C\/h2\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EDistinguishing among the various causes of left ventricular hypertrophy (LVH)\u2014physiologic conditions, metabolic diseases, or genetic syndromes\u2014can be a challenge, said Prof. McKenna. He pointed out that the majority of individuals carrying a disease-causing gene do not have the \u201cclassic presentation\u201d of HCM, ie, structural or hemodynamic evidence of LVH on echocardiography. Instead, the diagnosis of familial HCM relies on the microscopic evidence of myocyte disarray, which has been found even in individuals in whom the heart weight and left wall thickness are normal.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EGenetic Mutations in HCM\u003C\/h2\u003E\n         \u003Cp id=\u0022p-4\u0022\u003ETwelve genes have been identified in HCM. The most important of these are beta-myosin heavy chain and myosin-binding protein C, each of which accounts for 15\u201330% of cases of familial HCM. Troponin T and troponin I account for 5% and 4% of cases, respectively. The literature suggests that HCM is genetically and phenotypically heterogeneous, said Prof. McKenna, but he believes that HCM caused by different mutations are related disorders. To support his belief, he described cases that illustrated the similarities and differences of the four most common HCM-related genetic mutations.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EWith beta-myosin heavy chain mutations, there is allelic heterogeneity in relation to morphology, symptoms, and prognosis, with manifestations that range from mild to severe. However, Prof. McKenna noted, \u201cThe heterogeneity is between the genes, not within the families.\u201d Disease expression is homogeneous within each family, he explained. Thus, if a parent has mild disease, an offspring will have mild disease. In contrast, disease expression with troponin I mutation is heterogeneous within a family. \u201cYou can\u0027t predict the risk for the offspring on the basis of the parent. If the parent has mild disease, you can\u0027t assume that the child will have mild disease as well,\u201d he said.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EWith troponin T mutations, symptoms are mild or even absent. However, the prognosis is poor, with a risk of premature sudden death. He added that postmortem analyses of cardiac tissue have shown 2 to 3 times the amount of myocyte disarray, indicating that this finding may be a marker of electrical instability in patients with troponin T mutation.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EMyosin-binding protein C mutations are also homogeneous within families, but unlike the other disease-causing genes, this gene is associated with late-onset disease expression. Prof. McKenna said that the disease associated with this mutation has been referred to as mild; however, he pointed out, \u201cIt\u0027s mild only in that it occurs late in life. Once it manifests, the patient has the same disease-related complications, including arrhythmias, emboli, and sudden death.\u201d\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EInfluence of Mutation Analysis on Management\u003C\/h2\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EHow is mutation analysis applied in clinical practice? Prof. McKenna described a pathway for testing that involves carrying out mutation analysis on first-degree relatives when a mutation is detected in an individual (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). \u201cIf a mutation is found, you know that serial follow-up has merit,\u201d he said. If no mutation is found, the patient is discharged. Genetic counseling should be offered when testing demonstrates troponin I or beta-myosin heavy chain mutations. Perhaps the most important illustration of how knowledge of a specific mutation influences management is the identification of an individual with a troponin T mutation and being able to avoid premature sudden death with an implantable defibrillator.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/5\/7\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Molecular Diagnostics in Clinic.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-546592880\u0022 data-figure-caption=\u0022Molecular Diagnostics in Clinic.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/5\/7\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/5\/7\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/5\/7\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11258\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-9\u0022 class=\u0022first-child\u0022\u003EMolecular Diagnostics in Clinic.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-5\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EAdvantages and Disadvantages of Mutation Analysis\u003C\/h2\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EDetermining a molecular diagnosis of familial HCM has many advantages as well as some disadvantages, said Prof. McKenna. The targeted management allowed by a molecular diagnosis is cost-effective, as serial follow-up is done only when warranted by risk. Diagnostic uncertainty and false-negative clinical evaluations are also avoided, leading to better psychological well-being for patients. The primary disadvantage is related to the complexity of testing. For example, genetic data are difficult to interpret, an individual may have more than one disease-causing gene, and evaluation of entire families is needed. In addition, the approach requires that cardiologists work with genetic counselors and other specialists. \u201cWe will need new models of care,\u201d he said.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2007 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/7\/5\/7.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzm8dp\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzm8dp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}