scholarly journals Implications of Genetic Testing in Dilated Cardiomyopathy

2020 ◽  
Vol 13 (5) ◽  
pp. 476-487
Author(s):  
Job A.J. Verdonschot ◽  
Mark R. Hazebroek ◽  
Ingrid P.C. Krapels ◽  
Michiel T.H.M. Henkens ◽  
Anne Raafs ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Risk Factor ◽  
Ventricular Tachycardia ◽  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Atrioventricular Block ◽  
Gene Variants ◽  
Gene Variant ◽  
Nonsustained Ventricular Tachycardia ◽  
Pathogenic Gene

Background: Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome. Methods: This study included 689 patients with DCM from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies, and Holter monitoring. Upon detection of a pathogenic variant in a patient with DCM, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization, and/or occurrence of life-threatening arrhythmias. Results: A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in nonfamilial DCM. Family segregation analysis showed familial disease in 46% of patients with DCM who were initially deemed nonfamilial by history. Overall, 18% of patients with a nongenetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block and inversely correlated with the presence of a left bundle branch block ( P <0.01). After a median follow-up of 4 years, event-free survival was reduced in genetic versus patients with nongenetic DCM ( P =0.01). This effect on outcome was mediated by the associated electrical phenotypes of genetic DCM ( P <0.001). Conclusions: One in 5 patients with an established nongenetic risk factor or a nonfamilial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM.

scholarly journals The Frequency, Penetrance and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants

2021 ◽  
Author(s):  
Ravi Shah ◽  
Babken Asatryan ◽  
Ghaith Sharaf Dabbagh ◽  
Nay Aung ◽  
Mohammed Y Khanji ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Adult Population ◽  
Variant Calling ◽  
Gene Variants ◽  
Uk Biobank ◽  
Ventricular Dilation ◽  
Negative Results ◽  
Pathogenic Variants ◽  
The Uk ◽  
Pathogenic Gene

Background: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general, adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional and arrhythmic disease features. Methods: UK Biobank participants who had undergone whole exome sequencing (WES), ECG and cardiovascular magnetic resonance (CMR) imaging were selected for study. Three different variant calling strategies (one primary and two secondary) were used to identify subjects with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded to either 1) DCM (clinical or CMR diagnosis); 2) early DCM features, including arrhythmia and/or conduction disease, isolated ventricular dilation, and hypokinetic non-dilated cardiomyopathy; or 3) phenotype-negative. Results: Among 18,665 individuals included in the study, 1,463 (7.8%) subjects possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and CMR analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in 15.9% of individuals with putative pathogenic variants. Arrhythmias and/or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic non-dilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all three variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes, as compared to those with variants in moderate/limited evidence genes. Conclusions: In the UK Biobank, approximately 1/6 of adults with putative pathogenic variants in DCM genes exhibited a subclinical phenotype based on ECG and/or CMR, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation/dysfunction.

scholarly journals Estimating the penetrance of pathogenic gene variants in families with missing pedigree information

2018 ◽  
Vol 28 (10-11) ◽  
pp. 2924-2936 ◽  
Author(s):  
Marianne A Jonker ◽  
Johannes A Rijken ◽  
Frederik J Hes ◽  
Hein Putter ◽  
Erik F Hensen
Keyword(s):  
Disease Risk ◽  
Pedigree Information ◽  
Data Sets ◽  
Gene Variants ◽  
Gene Variant ◽  
Pedigree Structure ◽  
Family Based ◽  
Disease Free ◽  
Pathogenic Gene ◽  
The Way

Accurate assessment of the age-dependent disease risk conferred by germline variants in disease susceptibility genes is often hampered by the way the data are collected. Cohort-based data sets frequently contain an overrepresentation of patients (i.e. carriers of the gene variant of interest affected with the associated disease), and an underrepresentation of disease-free carriers. In order to overcome this problem, penetrance estimates can be based on family-based study designs, through the evaluation of index patients and their family members. This approach facilitates the identification of asymptomatic germline variant carriers. By adjusting for the way these family data are ascertained, an estimate for the penetrance of the pathogenic gene variant can be obtained. However, the family structure is often incomplete or missing. This complicates the estimation of the penetrance, because full adjustment of the likelihood is not possible. We present a conditional likelihood for the estimation of the penetrance of pathogenic gene variants, based on a cohort of multiple families comprising index patients, disease-free and affected non-index carriers, but with missing information on pedigree structure. The proposed estimator corrects for the ascertainment in a robust way and is shown to be more accurate than the frequently used Kaplan–Meier estimator of the penetrance function.

scholarly journals Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias

2018 ◽  
Vol 90 (3) ◽  
pp. 268-271 ◽  
Author(s):  
Puja R Mehta ◽  
Ashley R Jones ◽  
Sarah Opie-Martin ◽  
Aleksey Shatunov ◽  
Alfredo Iacoangeli ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Ascertainment Bias ◽  
Gene Variants ◽  
Gene Variant ◽  
Younger Age ◽  
Sporadic Als ◽  
The Mean ◽  
Familial Als ◽  
Lateral Sclerosis ◽  
Pathogenic Gene

ObjectiveAmyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease of motor neurons with a median survival of 2 years. Familial ALS has a younger age of onset than apparently sporadic ALS. We sought to determine whether this younger age of onset is a result of ascertainment bias or has a genetic basis.MethodsSamples from people with ALS were sequenced for 13 ALS genes. To determine the effect of genetic variation, age of onset was compared in people with sporadic ALS carrying a pathogenic gene variant and those who do not; to determine the effect of family history, we compared those with genetic sporadic ALS and familial ALS.ResultsThere were 941 people with a diagnosis of ALS, 100 with familial ALS. Of 841 with apparently sporadic ALS, 95 carried a pathogenic gene variant. The mean age of onset in familial ALS was 5.3 years younger than for apparently sporadic ALS (p=6.0×10−5, 95% CI 2.8 to 7.8 years). The mean age of onset of genetic sporadic ALS was 2.9 years younger than non-genetic sporadic ALS (p=0.011, 95% CI 0.7 to 5.2 years). There was no difference between the mean age of onset in genetic sporadic ALS and familial ALS (p=0.097).ConclusionsPeople with familial ALS have an age of onset about 5 years younger than those with apparently sporadic ALS, and we have shown that this is a result of Mendelian gene variants lowering the age of onset, rather than ascertainment bias.

Prevention of Arterial and Pulmonary Embolism by Oral Anticoagulants in Patients with Dilated Cardiomyopathy

1985 ◽  
Vol 54 (02) ◽  
pp. 521-523 ◽  
Author(s):  
P A Kyrle ◽  
C Korninger ◽  
H Gössinger ◽  
D Glogar ◽  
K Lechner ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Pulmonary Embolism ◽  
Risk Factor ◽  
Dilated Cardiomyopathy ◽  
Major Bleeding ◽  
Oral Anticoagulants ◽  
International Normalized Ratio ◽  
Moderate Intensity ◽  
Bleeding Complications ◽  
Arterial Embolism

SummaryThe incidence of arterial embolism (AE) and pulmonary embolism (PE) during treatment with oral anticoagulants (OA) or without OA therapy was studied in 38 patients with dilated cardiomyopathy (DCMP). AE/PE occurred in 17 patients (44.7%) before initiation of OA treatment. The severity of DCMP was a risk factor for AE/PE, but not the presence of atrial fibrillation or intracardial thrombi. No AE/PE episodes occurred during the period of OA therapy. No major bleeding complications were seen, probably due to the moderate intensity of OA therapy (therapeutic range 5-15% Thrombotest® [TT], 2.1-4.8 International Normalized Ratio [INR], median TT value 11%, median INR 2.6). Recurrence of AE was observed in 4 of 5 patients in whom treatment with OA had been discontinued.

scholarly journals EXPRESSION OF TRANSFORMING GROWTH FACTOR ALPHA BAMHI AND RSAI GENE VARIANTS ASSOCIATED WITH NON-SYNDROMIC CLEFT PALATE OF INDONESIAN SUBJECTS USING POLYMERASE CHAIN REACTION METHOD

2018 ◽  
Vol 11 (4) ◽  
pp. 351
Author(s):  
Ani Melani Maskoen ◽  
Saskia L Nasroen ◽  
Prima Nanda Fauziah ◽  
Eky Setiawan Soeria Soemantri ◽  
Basri A Gani
Keyword(s):  
Polymerase Chain Reaction ◽  
Risk Factor ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Alpha ◽  
Gene Variants ◽  
Gene Variant ◽  
Chain Reaction ◽  
Factor Alpha ◽  
Polymerase Chain

 Objective: This study aimed to detect and analyze transforming growth factor alpha (TGFA) BamHI and RsaI gene variants which associated with the risk factor of non-syndromic cleft palate only (NS CPO) of Indonesian subject.Methods: This was case-control study using samples from 32 NS CPO subjects and 28 control subjects. DNA was extracted from venous blood, and the TGFA gene was amplified using polymerase chain reaction technique, then digestion product from TaqI and RsaI restriction enzyme was evaluated. Statistical analysis to determine significant differences of gene variant frequency among NS CPO subject and control was χ2. The odds ratio (OR) was used to determine a risk factor of NS CPO.Results: The study results showed that the TGFA BamHI gene variant was not identified in NS CPO among Indonesian but TGFA RsaI gene variant was identified. The frequency of TT/B1B1 homozygous mutant genotype was 80.0% in NS CPO subjects and 20.0% in control subjects (OR=3.857; 95% confidence interval=0.405–36.749).Conclusion: TGFA RsaI gene can be considered a risk factor of NS CPO compared TGFA BamH1 gene of Indonesian subjects.

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