Titin Mutation in Familial Restrictive Cardiomyopathy ☆ Yael Peled a,1 , Michael Gramlich b,c,1 , Guy Yoskovitz a,d,1 , Micha S. Feinberg a , Arnon Afek e , Sylvie Polak-Charcon e , Elon Pras d , Ben-Ami Sela f , Eli Konen g , Omer Weissbrod h , Dan Geiger h , Paul M.K. Gordon i , Ludwig Thierfelder b , Dov Freimark a , Brenda Gerull b,j,2 , Michael Arad a,2 a Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel b Max Delbrueck Center for Molecular Medicine, Berlin, Germany c Department of Cardiology, University of Tuebingen, Germany d Gertner Institute of Medical Genetics, Tel Aviv University, Tel Aviv, Israel e Department of Pathology, Tel Aviv University, Tel Aviv, Israel f Institute of Chemical Pathology, Tel Aviv University, Tel Aviv, Israel g Department of Diagnostic Imaging, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel h Computer Science Department, The Technion, Haifa, Israel i Alberta Children's Hospital Research Institute Genomics and Bioinformatics Facility, University of Calgary, Calgary, Canada j Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada abstract article info Article history: Received 2 April 2013 Received in revised form 6 November 2013 Accepted 17 November 2013 Available online 25 November 2013 Keywords: Restrictive cardiomyopathy Heart failure Titin Autosomal dominant Diastolic Background: Familial restrictive cardiomyopathy (RCM) caused by a single gene mutation is the least common of the inherited cardiomyopathies. Only a few RCM-causing mutations have been described. Most mutations causing RCM are located in sarcomere protein genes which also cause hypertrophic cardiomyopathy (HCM). Other genes associated with RCM include the desmin and familial amyloidosis genes. In the present study we describe familial RCM with severe heart failure triggered by a de novo mutation in TTN, encoding the huge muscle filament protein titin. Methods and results: Family members underwent physical examination, ECG and Doppler echocardiogram stud- ies. The family comprised 6 affected individuals aged 12–35 years. Linkage to candidate loci was performed, followed by gene sequencing. Candidate loci/gene analysis excluded 18 candidate genes but showed segregation with a common haplotype surrounding the TTN locus. Sequence analysis identified a de novo mutation within exon 266 of the TTN gene, resulting in the replacement of tyrosine by cysteine. p.Y7621C affects a highly conserved region in the protein within a fibronectin-3 domain, belonging to the A/I junction region of titin. No other disease-causing mutation was identified in cardiomyopathy genes by whole exome sequencing. Conclusions: Our study shows, for the first time, that mutations in TTN can cause restrictive cardiomyopathy. The giant filament titin is considered to be a determinant of a resting tension of the sarcomere and this report provides genetic evidence of its crucial role in diastolic function. © 2013 Elsevier Ireland Ltd. All rights reserved. Introduction Restrictive cardiomyopathy (RCM) is a primary disease of the myocardium characterized by restrictive ventricular physiology and increased filling pressures that cause progressive left- and right-sided heart failure. The main features are marked atrial enlargement, normal-to-reduced ventricular diastolic volumes and normal ventricu- lar wall thickness [1–3]. By definition, systolic function is supposed to be normal or preserved in RCM, but contractility is often abnormal [3]. The overall prognosis is poor, especially with childhood onset, and patients often require cardiac transplantation. RCM may be found in systemic disorders causing abnormal substrate deposition, infiltration and fibrosis; it may also result from metastatic cancer, drug or radiation toxicity [1]. However, even after comprehensive work-up, including endomyocardial biopsy, many cases remain idiopathic. Some of these cases have a familial, genetically determined, etiology. Familial RCM caused by a single gene defect is the least common of the heritable cardiomyopathies encountered in clinical practice. The mode of inheritance is often autosomal dominant, but may also be autosomal recessive and X-linked. In some families the disease is caused by mutations in sarcomeric proteins such as troponin I, β-myosin heavy chain, troponin T and α-cardiac actin [3–6]. Other genes associated with RCM include the desmin and familial amyloidosis genes (primarily TTR). Mutations in desmin account for some of the dominantly or recessively inherited cases [7], and are characterized by a concomitant conduction International Journal of Cardiology 171 (2014) 24–30 ☆ “The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation”. E-mail address: michael.arad@sheba.health.gov.il (M. Arad). 1 The first 3 authors equally contributed to this work. 2 The last 2 authors equally contributed to this work. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.037 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard