Clinical Characteristics of 304 Kindreds Evaluated for Familial Dilated Cardiomyopathy

Kushner, Jessica D.; Nauman, Deirdre; Burgess, Donna; Ludwigsen, Susan; Parks, Sharie B.; Pantely, George A.; Burkett, Emily; Hershberger, Ray E.

doi:10.1016/j.cardfail.2006.03.009

Cited by 39 publications

(71 citation statements)

References 28 publications

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“…The investigation included 312 probands (290 Caucasians, of whom seven were of Hispanic descent; 16 African-Americans, three Asians and three Native Americans/Alaskan Natives) and used methods of clinical categorization of DCM as previously described 14. Clinical data were obtained through our own evaluations, which included minimally a history and physical examination, an electrocardiogram (ECG) and an echocardiogram as previously described15 or through medical record or death certificate review.…”

Section: Methodsmentioning

confidence: 99%

“…Clinical data were obtained through our own evaluations, which included minimally a history and physical examination, an electrocardiogram (ECG) and an echocardiogram as previously described15 or through medical record or death certificate review. DCM was defined as left ventricular enlargement (LVEDD ≥95th percentile or Z score >1.65) of a gender- and height-matched Framingham population 16 with systolic dysfunction (left ventricular ejection fraction less than or equal to 50%), and the exclusion of other possible causes of cardiomyopathy, meeting diagnostic criteria consistent with idiopathic dilated cardiomyopathy (IDC) 14, 17. Familial dilated cardiomyopathy (FDC) was assigned in cases with a documented diagnosis of IDC in two or more family members 14, 17.…”

Section: Methodsmentioning

confidence: 99%

“…DCM was defined as left ventricular enlargement (LVEDD ≥95th percentile or Z score >1.65) of a gender- and height-matched Framingham population 16 with systolic dysfunction (left ventricular ejection fraction less than or equal to 50%), and the exclusion of other possible causes of cardiomyopathy, meeting diagnostic criteria consistent with idiopathic dilated cardiomyopathy (IDC) 14, 17. Familial dilated cardiomyopathy (FDC) was assigned in cases with a documented diagnosis of IDC in two or more family members 14, 17. Family members with some cardiovascular abnormality but not meeting criteria for DCM were categorized as unknown.…”

Section: Methodsmentioning

confidence: 99%

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Identification of Novel Mutations in RBM20 in Patients with Dilated Cardiomyopathy

Morales

Gonzalez-Quintana

et al. 2010

Clinical Translational Sci

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169

191

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IntroductionDilated cardiomyopathy (DCM; OMIM 115200) is a debilitating primary cardiac muscle disease with a 5-year mortality approaching 50% following diagnosis.1,2 Whether familial or sporadic, DCM shows remarkably high genetic heterogeneity. 3,4 To date, the molecular basis of most of DCM cases remains unknown despite the fact that mutations in more than 30 genes have been shown to be disease causing or disease associated. 5,6 Because of this marked locus heterogeneity, the fraction of DCM patients who have a mutation in any one gene is small, and ranged from 0.3% to 5.9% in our recent resequencing studies. [7][8][9][10] Most of the genes with mutations causing DCM encode for sarcomeric proteins involved in contraction, or cytoskeletal proteins important for cell structure or force transduction. 5,6 Exceptions to this include a mutation identifi ed in the eye absent transcription factor 4 (EYA4) in a family with both DCM and sensorineural hearing loss, 11 and mutations in the genes encoding presenilin 1 and 2 ( PSEN1 and PSEN2 ) that we recently identifi ed in DCM families.10 Although the pathogenic mechanisms of EYA4 and the presenilins in DCM remain to be defi ned, both are known to play regulatory roles in the heart even though they are neither essential structural components nor contractile proteins.A recent genetic linkage and gene-mapping study demonstrated that mutations in RBM20 , a ribonucleic acid (RNA)-binding protein gene, cause DCM.12 Th is discovery is intriguing in several aspects. To our knowledge, this is the fi rst report to suggest that a genetic abnormality of an RNA-binding protein can lead to cardiomyopathy.13 It is also noteworthy that RBM20 mutations were associated with severe cases of DCM with high mortality and patients needing heart transplantation. Moreover, the fi ve mutations identifi ed in the fi rst report were concentrated in a small region of RBM20, spanning only fi ve amino acids, and encoded by a single exon. 12To further evaluate the role of RBM20 in DCM pathogenesis and the DCM clinical characteristics caused by RBM20 mutations, we genetically screened a cohort of 312 DCM probands, and their family members when a mutation was identifi ed. We found six unique mutations in six unrelated probands, four of which were novel. Th ese results expand the RBM20 mutation spectrum in DCM and further emphasize the importance of RBM20 in the myocardial disease. Materials and Methods Clinical evaluationWritten, informed consent was obtained from all subjects, and the Institutional Review Boards at the Oregon Health & Science University and the University of Miami approved the study. Th e investigation included 312 probands (290 Caucasians, of whom 7 were of Hispanic descent; 16 African-Americans, 3 Asians and 3 Native Americans/Alaskan Natives) and used methods of clinical categorization of DCM as previously described.14 Clinical data were obtained through our own evaluations, which included minimally a history and physical examination, an electrocardiogram (ECG) and an echocardiogram...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Identification of Novel Mutations in RBM20 in Patients with Dilated Cardiomyopathy

Morales

Gonzalez-Quintana

et al. 2010

Clinical Translational Sci

Self Cite

169

191

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“…The study included 324 unrelated IDC probands, and used methods of clinical categorization previously described. 10 For this study, families with confirmed and probable familial disease 10 were classified as FDC; those with a negative family history or possible FDC 10 were classified as IDC. In FDC cases, the patient and at least one first or second degree relative had confirmed IDC, defined as left ventricular enlargement (LVE) with systolic dysfunction after the exclusion of other detectable causes of DCM including coronary artery disease (CAD).…”

Section: Patient Populationmentioning

confidence: 99%

Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy

Parks

Kushner

Nauman

et al. 2008

American Heart Journal

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217

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“…2) (9). In addition, the age of onset of DCM varies widely, and ranged from 0 to 75 years in a familial DCM cohort from our group (10). Thus, even in family members genetically at risk to carry a DCM mutation, their DCM may not have yet presented and can only be identified with prospective clinical screening.…”

Section: Dcm and Its Relationship To Hf: Phenomics And Genomics Consimentioning

confidence: 95%

Where Genome Meets Phenome: Rationale for Integrating Genetic and Protein Biomarkers in the Diagnosis and Management of Dilated Cardiomyopathy and Heart Failure

Piran

Liu

Morales

et al. 2012

Journal of the American College of Cardiology

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This review provides the rationale for integrating genomic and protein biomarkers in the evolving diagnosis and management of dilated cardiomyopathy (DCM) and its causal pathway to heart failure (HF), with a larger objective to serve as a template for genomic and phenomic profiling of other cardiovascular disease. DCM is a major cause of HF and accounts for more than half of heart transplantation in adults and children worldwide. DCM may remain asymptomatic for years, but HF and/or arrhythmias, both late manifestations of the disease, ultimately cause significant morbidity and mortality. A significant proportion of DCM has a genetic etiology. DCM can also result from environmental injury such as infection, toxins, or catecholamine excess. While molecular genetic testing can identify those at risk for genetic DCM, epigenetic and sentinel phenomic staging can help to identify those at highest risk in need for intervention. Phenomic staging includes integrating clinical and imaging features, transcriptomics, higher order proteomics and metabolomics interactions, and epidemiological data. This principle can be applied in family members of patients with DCM, where genetic testing and clinical phenotyping are indicated. This will allow the design of specific interventions tailored to individuals sharing similar risks, to alter the natural history of DCM and obviate complications such as HF/arrhythmias.

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Clinical Characteristics of 304 Kindreds Evaluated for Familial Dilated Cardiomyopathy

Cited by 39 publications

References 28 publications

Identification of Novel Mutations in RBM20 in Patients with Dilated Cardiomyopathy

Identification of Novel Mutations in RBM20 in Patients with Dilated Cardiomyopathy

Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy

Where Genome Meets Phenome: Rationale for Integrating Genetic and Protein Biomarkers in the Diagnosis and Management of Dilated Cardiomyopathy and Heart Failure

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