Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomyopathies

Meder, Benjamin; Haas, Jan; Keller, Andreas; Heid, Christiane; Just, Steffen; Borries, Anne; Boisguérin, Valesca; Scharfenberger-Schmeer, Maren; Stähler, Peer F.; Beier, Markus; Weichenhan, Dieter; Strom, Tim M.; Pfeufer, Arne; Korn, Bernhard; Katus, Hugo A.; Rottbauer, Wolfgang

doi:10.1161/circgenetics.110.958322

Cited by 159 publications

(115 citation statements)

References 56 publications

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“…These technologies have also enabled testing of panels of genes in HCM. 14 The increase in available genetic information and the greater number of HCM families undergoing comprehensive genetic testing may alter the classification of pathogenicity of previously described HCM mutations. This study sought to reassess SNV classification in HCM probands in the setting of recent availability of population genetic information, in a specialized multidisciplinary clinic setting.…”

Section: Introductionmentioning

confidence: 99%

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Ingles

Bagnall

et al. 2014

Genetics in Medicine

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Purpose: Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Methods:Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current populationbased allele frequencies.Results: From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Conclusion:Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.

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Section: Introductionmentioning

confidence: 99%

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Ingles

Bagnall

et al. 2014

Genetics in Medicine

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“…In case of trxr-2 which is present in an operon including two additional genes of unc-32 and tpx-1, we constructed two transcriptional and translational expression plasmids driven by either external operon promoter (pEX) or internal promoter (pIN) adjacent to the coding region of trxr-2, because internal promoters also can drive gene expression (Meder et al, 2011). A transcriptional GFP expression construct driven by trxr-1 promoter was expressed only in M2 (Figs.…”

Section: Resultsmentioning

confidence: 99%

Two Thioredoxin Reductases, trxr-1 and trxr-2, Have Differential Physiological Roles in Caenorhabditis elegans

Bandyopadhyay

Hwaang

et al. 2012

Molecules and Cells

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“…The benefits of Next Generation Sequencing in terms of a more comprehensive genetic analysis (more extended set of genes, including genetic modifiers) with a potential time-costs optimization, will be potentially striking for HCM and inherited heart diseases, in general. 11 …”

Section: Discussionmentioning

confidence: 99%

An Unusual Case of Familial Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: A Still Unsolved Diagnosis

et al. 2012

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A 35-year-old woman was referred to our centre for clinical management of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) systolic dysfunction (end-stage evolution). She was recently diagnosed elsewhere because of palpitations. Her 7-year-old daughter underwent familiar screening and she was diagnosed with classic HCM. She was completely asymptomatic without extracardiac or systemic manifestations. During the following years, they both experienced a similar clinical course with worsening dyspnoea and progressive deterioration of LV systolic function. They both underwent heart transplantation, the mother at the age of 47 and the daughter at the age of 23, respectively. Many diagnostic hypotheses, including sarcomeric HCM, Anderson-Fabry disease, glycogen storage diseases and mitochondrial cardiomyopathies have been taken into account. The diagnostic work-up included serial electrocardiogram and echocardiographic assessments, pathologic evaluation of the explanted hearts and genetic analysis of 8 sarcomeric and 3 metabolic genes. Even if a shared HCM phenotype (LV systolic dysfunction in two first-degree female family members associated with a likely autosomal dominant inheritance and absence of extracardiac or multisystemic manifestations) could support a temptative diagnosis of sarcomeric HCM, a definitive diagnosis could not be reached, due to the lack of genetic analysis to confirm such diagnosis. Case ReportA 35-year-old woman was referred to our centre for clinical management of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) systolic dysfunction (end-stage phase). This condition was recently diagnosed in a different hospital because of palpitations.The electrocardiogram (ECG) showed sinus rhythm and negative T waves in the lateral leads ( Figure 1A). Echocardiography showed LV hypertrophy (maximal wall thickness 14 mm) associated with LV enlargement (enddiastolic diameter 56 mm) and LV ejection fraction (EF) of 30%. Of note, a relative wall thinning localized at the basal segment of the interventricular septum with marked akinesia was present ( Figure 1B and 1C, arrows). At that time she was mildly symptomatic, showing dyspnoea on mild efforts (NYHA functional class II). No other clinical manifestations were present and laboratory parameters were unremarkable. Medical therapy with beta-blockers and ACE-inhibitors was started.The patient's 7-year-old daughter underwent familiar screening with ECG and echocardiography. She was completely asymptomatic. No mental retardation or other extracardiac manifestations were detected and laboratory parameters were normal. The ECG showed extreme LV hypertrophy with infero-lateral pseudonecrosis and negative T waves in the infero-lateral leads (Figure 2A). Two-dimensional echocardiography disclosed a classical form of HCM with a maximal wall thickness of 16 mm at the postero-lateral wall level, a LV end-diastolic diameter of 35 mm and a LV ejection fraction of 78%. As the mother, a relative and localized wall thinning associated with hypo...

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Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomyopathies

Cited by 159 publications

References 56 publications

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Two Thioredoxin Reductases, trxr-1 and trxr-2, Have Differential Physiological Roles in Caenorhabditis elegans

An Unusual Case of Familial Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: A Still Unsolved Diagnosis

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