Abstract 13962: Large Exome Data Questions the Role of 14 Genes Previously Associated With Dilated Cardiomyopathy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Nina Nouhravesh ◽  
Gustav Alhberg ◽  
Peter E Weeke ◽  
Morten S Olesen
Keyword(s):  
Dilated Cardiomyopathy ◽  
Genetic Variants ◽  
Human Gene ◽  
Splice Variants ◽  
Population Based ◽  
Allele Frequencies ◽  
Exome Data ◽  
Monogenic Form ◽  
Mutation Database

Background: Dilated cardiomyopathy (DCM) has been associated with hundreds of genetic variants across 62 genes. These associations are now being questioned by large control populations in which these variants are found with high allele frequencies. Hypothesis: We hypothesized that genetic variants previously associated with DCM are overrepresented in the population-based ExAC database when taking the prevalence of the disease into account. Hence, we aimed to identify potentially false-positive variants previously associated with DCM. Methods: We identified all previously DCM associated variants in The Human Gene Mutation Database (HGMD). We then systematically searched for these in the ExAC database containing exome data on 61.000 individuals. In addition, we performed a PolyPhen-2 prediction on all variants, including those not found in the ExAC database. Results: We identified 148 (31%) out of 473 variants previously associated with DCM in ExAC. These variants included eight stop-gain variants, eight splice variants and 132 missense variants. The 148 variants affected 7.928 alleles corresponding to a genotype prevalence of 1:7 in the ExAC population. Thirty-five variants were found in 25 or more alleles, corresponding to a DCM genotype prevalence of 1:8 Furthermore, we identified all variants previously associated with DCM in 14 genes; hereof 4 genes only contained variants above our estimated allele frequency (25:61000). Polyphen-2 analysis predicted 53 (36%) variants to be benign in the ExAC population compared with 53 (16%) among variants not found in ExAC (p<0.001). Conclusion: In conclusion, we identified much higher genotype prevalence of previously DCM associated variants than expected in the exome data from ExAC. More importantly we found 4 genes in which all previously identified variants were found with relative high allele frequencies, questioning the association of these genes with the monogenic form of DCM.

scholarly journals New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants

2013 ◽  
Vol 21 (9) ◽  
pp. 918-928 ◽  
Author(s):  
Charlotte Andreasen ◽  
Jonas B Nielsen ◽  
Lena Refsgaard ◽  
Anders G Holst ◽  
Alex H Christensen ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Population Based ◽  
Exome Data

MS282 ROLE OF SUSCEPTIBILITY GENETIC VARIANTS AND ENVIRONMENTAL FACTORS IN OBESITY RISK IN TWO SPANISH POPULATION BASED STUDIES

2010 ◽  
Vol 11 (2) ◽  
pp. 166
Author(s):  
F.J. Chaves ◽  
M.L. Mansego ◽  
S. Morcillo ◽  
G. Rojo ◽  
F. Martínez ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Genetic Variants ◽  
Population Based ◽  
Spanish Population ◽  
Obesity Risk

scholarly journals New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome

BMC Genetics ◽  
2014 ◽  
Vol 15 (1) ◽  
pp. 74 ◽  
Author(s):  
Ren-Qiang Yang ◽  
Javad Jabbari ◽  
Xiao-Shu Cheng ◽  
Reza Jabbari ◽  
Jonas B Nielsen ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Genetic Variants ◽  
Population Based ◽  
Exome Data

The role of dyslipidemia in idiopathic dilated cardiomyopathy

2008 ◽  
Vol 7 ◽  
pp. 29-29
Author(s):  
M SKWAREK ◽  
Z BILINSKA ◽  
L MAZURKIEWICZ ◽  
J GRZYBOWSKI ◽  
M KRUK ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Idiopathic Dilated Cardiomyopathy

scholarly journals Case–Parent Trio Studies in Cleft Lip and Palate

2020 ◽  
Vol 07 (03) ◽  
pp. 075-079
Author(s):  
Mahamad Irfanulla Khan ◽  
Prashanth CS
Keyword(s):  
Genetic Variants ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Geographical Location ◽  
Genetic Association Studies ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Family Based ◽  
Study Designs

AbstractCleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations in humans involving various genetic and environmental risk factors. The prevalence of CL/P varies according to geographical location, ethnicity, race, gender, and socioeconomic status, affecting approximately 1 in 800 live births worldwide. Genetic studies aim to understand the mechanisms contributory to a phenotype by measuring the association between genetic variants and also between genetic variants and phenotype population. Genome-wide association studies are standard tools used to discover genetic loci related to a trait of interest. Genetic association studies are generally divided into two main design types: population-based studies and family-based studies. The epidemiological population-based studies comprise unrelated individuals that directly compare the frequency of genetic variants between (usually independent) cases and controls. The alternative to population-based studies (case–control designs) includes various family-based study designs that comprise related individuals. An example of such a study is a case–parent trio design study, which is commonly employed in genetics to identify the variants underlying complex human disease where transmission of alleles from parents to offspring is studied. This article describes the fundamentals of case–parent trio study, trio design and its significances, statistical methods, and limitations of the trio studies.

The role of cytochrome P450 enzyme genetic variants in cannabis hyperemesis syndrome—A case report

2021 ◽  
Author(s):  
Maxim Kuzin ◽  
Franziskos Xepapadakos ◽  
Isabel Scharrer ◽  
Marc Augsburger ◽  
Chin‐Bin Eap ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Case Report ◽  
Genetic Variants ◽  
Cytochrome P450 Enzyme ◽  
P450 Enzyme ◽  
Cannabis Hyperemesis Syndrome

The role of inflammation in recent-onset dilated cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Chaloupka ◽  
J Krejci ◽  
H Poloczkova ◽  
P Hude ◽  
E Ozabalova ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Left Ventricular ◽  
Pcr Analysis ◽  
Myocardial Inflammation ◽  
Gene Variants ◽  
Absolute Increase ◽  
Recent Onset ◽  
Cardiotropic Viruses

Abstract Background The aetiology of recent-onset dilated cardiomyopathy (RODCM) includes inflammatory, genetic, toxic and metabolic causes. Delineating the role of inflammation on the genetic background could improve risk stratification. Purpose We aimed to ascertain the role of inflammation evaluated by serum CRP immunohistochemical and PCR analysis of endomyocardial biopsy (EMB) in conjunction with genetic testing in left ventricular reverse remodelling (LVRR) in 12-month follow-up. Methods 83 RODCM patients enrolled in this prospective observational study underwent 12-month echocardiographic follow up whole-exome sequencing, and EMB. Presence of cardiotropic viruses was determined by PCR analysis of the EMB samples. Inflammation was defined according to TIMIC immunohistochemical criteria as the presence of &gt;7 CD3+ lymphocytes/mm2 and/or &gt;14 infiltrating leukocytes (LCA+ cells/mm2). LVRR was defined as an absolute increase in LV ejection fraction &gt; +10% and a relative decrease of LV end-diastolic diameter &gt;−10% at 12 months. Results LVRR occurred in 28 (34%) of all cases. PCR analysis uncovered cardiotropic viruses in 55 (66%) patients, with highest prevalence of parvovirus B19 (47%). (Figure 1) EMB analysis detected inflammation in 28 (34%) cases and inflammation significantly positively predicted LVRR (P=0.019). Sequencing identified disease-related gene variants (ACMG class 3–5) in 45 (54%) patients. Carriers of non-titin gene variants showed a lowest probability of 12-month LVRR (19%) P=0.041. Combination of genetic findings and inflammation did not improve the prediction of LVRR in 12 months. (Table 1) Conclusion Both myocardial inflammation and disease-causing variants can be identified in a large proportion of RODCM cases. Prognostic value of CRP and virus detection is low. Non-titin disease-related variants carriers of are less likely to reach LVRR. In contrast, myocardial inflammation detected by EMB predicts favourable remodelling in 12 months. Figure 1 Funding Acknowledgement Type of funding source: None

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