Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals

Kayvanpour, Elham; Sedaghat‐Hamedani, Farbod; Amr, Ali; Lai, Alan; Haas, Jan; Holzer, Daniel Benjamin; Frese, Karen; Keller, Andreas; Jensen, Katrin; Katus, Hugo A.; Meder, Benjamin

doi:10.1007/s00392-016-1033-6

Cited by 177 publications

(177 citation statements)

References 82 publications

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“…For DCM not caused by mutations in LMNA , identifying a genetic cause in a proband is often of limited importance for the individual but more relevant to the family in terms of cascade screening and family planning 21. This is not the case for LMNA mutations, given the higher prevalence of SCD, cardiac transplantation and ventricular arrhythmias compared with DCM caused by sarcomere gene mutations,22 the consequently lower threshold for prophylactic ICD implantation,23 and because therefore, the exclusion of an LMNA mutation is in itself reassuring 21…”

Section: Diagnosticsmentioning

confidence: 99%

“…Given the significant phenotypic pleiotropy observed in spite of mutational invariance across and within families with LMNA mutations, there is a risk for selection bias causing over-representation of the more severe LHD presentations in the published literature. Reports on milder and variable phenotypes such as that arising from the founder mutation p.(Arg331Gln)22 are therefore important. …”

Section: Diagnosticsmentioning

confidence: 99%

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Lamin and the heart

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Arbustini

Bonne

et al. 2017

Heart

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116

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Lamins A and C are intermediate filament nuclear envelope proteins encoded by the gene. Mutations in cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an mutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to exclude mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.

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Section: Diagnosticsmentioning

confidence: 99%

Section: Diagnosticsmentioning

confidence: 99%

Lamin and the heart

Captur

Arbustini

Bonne

et al. 2017

Heart

121

116

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“…In adult cohorts, sarcomeric genes are the major disease genes for HCM (>70%), DCM (14%, 35%, or 37%), and LVNC (26% or 29%) . In all CMP subgroups, patients carried most frequently VOI in sarcomere genes suggesting them as major contributor in pediatric CMP as previously shown in meta‐analyses for adult‐onset CMP . A detailed genotype‐phenotype correlation was not intended in this study of index‐patients due to the composition and small size of the subgroups per CMP.…”

Section: Discussionmentioning

confidence: 85%

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

et al. 2019

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The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.

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“…In 2009, mutations in the arginine/serine-rich domain (RS) of the RBM20 protein were identified as the cause of familial DCM in 8 families [3], and since then, several groups have confirmed the association of familial DCM with mutations in this particular domain [4-6], as well as with mutations outside the RS domain [4, 5, 7]. Nowadays, pathogenic mutations in RBM20 gene account for 2–3% of patients with idiopathic DCM [8]. Furthermore, mutations in the RS domain of RBM20 are associated with clinically aggressive DCM with high rates of heart failure and premature death [1, 6], high penetrance (94%) [6], conduction system disorders [8], a mean age of diagnosis at 33.8–39 years [6, 8], and a low mean age for heart transplantation at 28.5 years [8].…”

Section: Introductionmentioning

confidence: 99%

“…Nowadays, pathogenic mutations in RBM20 gene account for 2–3% of patients with idiopathic DCM [8]. Furthermore, mutations in the RS domain of RBM20 are associated with clinically aggressive DCM with high rates of heart failure and premature death [1, 6], high penetrance (94%) [6], conduction system disorders [8], a mean age of diagnosis at 33.8–39 years [6, 8], and a low mean age for heart transplantation at 28.5 years [8]. In this study, we report for the first time the co-segregation of the mutation NM_001134363.2:c.1900C>T, p.(Arg634Trp) in the RS domain of the RBM20 gene in 6 members of a family displaying considerable phenotypic heterogeneity, and this further supports the pathogenic role of this mutation.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic Heterogeneity within Members of a Family Carrying the Same <b><i>RBM20</i></b> Mutation R634W

et al. 2018

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Objective: We present the genotypic and phenotypic characterization of a family displaying dilated cardiomyopathy (DCM). Methods: The proband and his relatives underwent full cardiological assessment. Genetic analysis of the proband was performed with the use of next-generation sequencing technology. Results: In this study, we present 6 members of a family carrying the RBM20 mutation NM_001134363.2:c.1900C>T. The proband was initially diagnosed with DCM at the age of 18 years and received an implantable cardioverter defibrillator (ICD) due to ventricular arrhythmias. His brother, carrier of the mutation, has been diagnosed with borderline left ventricular function. The mutation was shown to be of paternal origin, but their father remains asymptomatic with a mild DCM, while his electrocardiogram at the initial evaluation showed a right bundle branch block pattern. The mutation was also detected in the index case’s aunt who was resuscitated from sudden cardiac death. Her echocardiography revealed early stages of DCM and a bicuspid aortic valve. Her children are both carriers of the mutation. Her daughter is unaffected, but her son has an ICD implanted due to sustained ventricular tachycardia and presents early signs of DCM. Conclusion: Our findings are the first report of co-segregation of the mutation in 6 family members, supporting its pathogenic role.

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Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals

Cited by 177 publications

References 82 publications

Lamin and the heart

Lamin and the heart

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

Phenotypic Heterogeneity within Members of a Family Carrying the Same <b><i>RBM20</i></b> Mutation R634W

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