title: Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations.
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.
authors.affiliation: Department of Medical Biology, Molecular Biology Laboratory, Institute of Cardiology, Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Franaszczyk
authors.affiliation: Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Chmielewski
authors.affiliation: Department of Medical Biology, Molecular Biology Laboratory, Institute of Cardiology, Warsaw, Poland.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Truszkowska
authors.affiliation: Department of Genetics, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Stawinski
authors.affiliation: Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Michalak
authors.affiliation: Department of Medical; Genetics, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rydzanicz
authors.affiliation: Department of Heart Failure and Transplantology, Institute of Cardiology, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Sobieszczanska-Malek
authors.affiliation: Department of Genetics, Institute of Physiology and Pathology of Hearing, Kajetany/Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Pollak
authors.affiliation: Department of Cardiomyopathies, Institute of Cardiology, Warsaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Szczygieł
authors.affiliation: Department of Medical; Genetics, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kosinska
authors.affiliation: Department of Cardiac Surgery and Transplantology, Institute of Cardiology, Warsaw, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Parulski
authors.affiliation: Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
authors.affiliation: Department of Heart Failure and Transplantology, Institute of Cardiology, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Tarnowska
authors.affiliation: Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Marcin M
authors.initials: MM
authors.lastname: Machnicki
authors.affiliation: Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland.
authors.forename: Bogna
authors.initials: B
authors.lastname: Foss-Nieradko
authors.affiliation: Department of Medical Biology, Molecular Biology Laboratory, Institute of Cardiology, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Szperl
authors.affiliation: Department of Cardiomyopathies, Institute of Cardiology, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sioma
authors.affiliation: Department of Cardiac Surgery and Transplantology, Institute of Cardiology, Warsaw, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Kusmierczyk
authors.affiliation: Department of Cardiomyopathies, Institute of Cardiology, Warsaw, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Grzybowski
authors.affiliation: Department of Heart Failure and Transplantology, Institute of Cardiology, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zielinski
authors.affiliation: Department of Medical; Genetics, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
authors.affiliation: Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland.
authors.forename: Zofia T
authors.identifier: http://orcid.org/0000-0003-1451-2069
authors.initials: ZT
authors.lastname: Bilinska
mesh_terms: D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D015331:Cohort Studies; D064211:Connectin / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation / Q000235:genetics*; D019683:Penetrance; D015995:Prevalence; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D064211:Connectin; D012333:RNA, Messenger