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      Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

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          Abstract

          TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants ( TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.

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          Most cited references 11

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          Atlas of the clinical genetics of human dilated cardiomyopathy.

          Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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            Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.

            We examined the prevalence, genotype-phenotype correlation, and natural history of lamin A/C gene (LMNA) mutations in subjects with dilated cardiomyopathy (DCM). Mutations in LMNA have been found in patients with DCM with familial conduction defects and muscular dystrophy, but the clinical spectrum, prognosis, and clinical relevance of laminopathies in DCM are unknown. A cohort of 49 nuclear families, 40 with familial DCM and 9 with sporadic DCM (269 subjects, 105 affected), was screened for mutations in LMNA using denaturing high-performance liquid chromatography and sequence analysis. Bivariate analysis of clinical predictors of LMNA mutation carrier status and Kaplan-Meier survival analysis were performed. Mutations in LMNA were detected in four families (8%), three with familial (R89L, 959delT, R377H) and one with sporadic DCM (S573L). There was significant phenotypic variability, but the presence of skeletal muscle involvement (p < 0.001), supraventricular arrhythmia (p = 0.003), conduction defects (p = 0.01), and "mildly" DCM (p = 0.006) were predictors of LMNA mutations. The LMNA mutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers. Mutations in LMNA cause a severe and progressive DCM in a relevant proportion of patients. Mutation screening should be considered in patients with DCM, in particular when clinical predictors of LMNA mutation are present, regardless of family history.
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              Does p.Q247X in TRIM63 cause human hypertrophic cardiomyopathy?

              Variants in TRIM63, including a nonsense mutation (p.Q247X), have been suggested recently to cause hypertrophic cardiomyopathy. To verify pathogenicity of TRIM63 p.Q247X detected by whole-exome sequencing in a symptomless professional sports player seeking medical advice because of a prolonged QT interval found during a routine check-up. Clinical studies were performed in the proband and his mother, who also carried TRIM63 p.Q247X. No evidence of hypertrophic cardiomyopathy was found in either person. The p.Q247X variant in TRIM63 is not likely to be a highly penetrant variant causing hypertrophic cardiomyopathy.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 January 2017
                2017
                : 12
                : 1
                Affiliations
                [1 ]Department of Medical Biology, Molecular Biology Laboratory, Institute of Cardiology, Warsaw, Poland
                [2 ]Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland
                [3 ]Department of Genetics, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland
                [4 ]Department of Medical; Genetics, Medical University of Warsaw, Warsaw, Poland
                [5 ]Department of Heart Failure and Transplantology, Institute of Cardiology, Warsaw, Poland
                [6 ]Department of Cardiomyopathies, Institute of Cardiology, Warsaw, Poland
                [7 ]Department of Cardiac Surgery and Transplantology, Institute of Cardiology, Warsaw, Poland
                [8 ]Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Warsaw, Poland
                [9 ]Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
                University of Texas MD Anderson Cancer Center, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: MF RP ZTB.

                • Data curation: MF PC GT PS EM MR A. Pollak JS JK TS MMM BFN AS MK.

                • Formal analysis: MF PC GT PS EM MR MSM A. Pollak JS JK A. Parulski TS AT MMM AS MK.

                • Investigation: MF PC GT EM MR MSM A. Pollak JS JK A. Parulski TS AT MMM BFN MS AS MK.

                • Methodology: MF PC RP ZTB.

                • Project administration: ZTB MF RP.

                • Resources: MF PC GT PS EM MR MSM A. Pollak JS JK A. Parulski TS AT MMM BFN MS AS MK JG TZ ZTB.

                • Software: PS MF GT.

                • Supervision: ZTB RP JG TZ.

                • Validation: MF ZTB RP PC RP GT PS MS.

                • Visualization: MF ZTB RP EM.

                • Writing – original draft: MF ZTB RP MMM.

                • Writing – review & editing: MF ZTB RP JG TZ.

                Article
                PONE-D-16-15330
                10.1371/journal.pone.0169007
                5207678
                28045975
                © 2017 Franaszczyk et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 4, Tables: 3, Pages: 14
                Product
                Funding
                Funded by: National Science Centre (PL)
                Award ID: 2011/01/B/NZ4/03455
                Award Recipient :
                Funded by: Institute of Cardiology (PL)
                Award ID: 2.56/II/2014
                Award Recipient :
                Funded by Institute of Cardiology grant No 2.56/II/2014 GT ( http://www.ikard.pl/home.html); National Science Centre Poland grants No 2013/11/N/NZ2/02528 MF and 2011/01/B/NZ4/03455 RP ( https://www.ncn.gov.pl/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Molecular biology
                Molecular biology techniques
                Sequencing techniques
                DNA sequencing
                Next-Generation Sequencing
                Research and analysis methods
                Molecular biology techniques
                Sequencing techniques
                DNA sequencing
                Next-Generation Sequencing
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Transcriptome Analysis
                Next-Generation Sequencing
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Transcriptome Analysis
                Next-Generation Sequencing
                Medicine and Health Sciences
                Diagnostic Medicine
                Medicine and Health Sciences
                Cardiology
                Heart Failure
                Medicine and Health Sciences
                Cardiology
                Cardiomyopathies
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Cardiovascular Procedures
                Cardiac Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Cardiac Transplantation
                Medicine and Health Sciences
                Cardiology
                Cardiomyopathies
                Dilated Cardiomyopathy
                Biology and Life Sciences
                Genetics
                Mutation
                Medicine and Health Sciences
                Clinical Genetics
                Custom metadata
                All relevant data is contained in the paper and supporting information files. Additionally, information that could be used to identify study participants is on request from the corresponding author at ( zbilinska@ 123456ikard.pl ).

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