Curr Heart Fail Rep DOI 10.1007/s11897-015-0271-7 BIOMARKERS OF HEART FAILURE (W H W TANG, SECTION EDITOR) Evolving Approaches to Genetic Evaluation of Specific Cardiomyopathies Loon Yee Louis Teo1 & Rocio T. Moran 2 & W. H. Wilson Tang 1,3 # Springer Science+Business Media New York 2015 Abstract The understanding of the genetic basis of cardiomy- Keywords Genetic evaluation . Cardiomyopathy . opathy has expanded significantly over the past 2 decades. Hereditary . Genetic testing . Evolving approaches The increasing availability, shortening diagnostic time, and lowering costs of genetic testing have provided researchers and physicians with the opportunity to identify the underlying Introduction genetic determinants for thousands of genetic disorders, in- cluding inherited cardiomyopathies, in effort to improve pa- In the contemporary definitions and classification of cardio- tient morbidities and mortality. As such, genetic testing has myopathies by the American Heart Association in 2006, car- advanced from basic scientific research to clinical application diomyopathies represent a heterogeneous group of diseases of and has been incorporated as part of patient evaluations for the myocardium associated with mechanical and/or electrical suspected inherited cardiomyopathies. Genetic evaluation dysfunction, and can be divided into primary cardiomyopa- framework of inherited cardiomyopathies typically encom- thies which predominantly involve the heart muscle, or sec- passes careful evaluation of family history, genetic counseling, ondary cardiomyopathies which are a result of generalized clinical screening of family members, and if appropriate, mo- systemic (multiorgan) disorders [1]. With the rapid evolution lecular genetic testing. This review summarizes the genetics, of molecular genetics in cardiology, the knowledge and liter- current guideline recommendations, and evidence supporting ature of the complex interplay between genetics and cardio- the genetic evaluation framework of five hereditary forms of myopathies have expanded significantly over the past few cardiomyopathy: dilated cardiomyopathy (DCM), hypertro- decades. Inherited cardiomyopathies (or Bprimary cardiomy- phic cardiomyopathy (HCM), arrhythmogenic right ventricu- opathies of genetic origin^) encompass a wide spectrum of lar cardiomyopathy (ARVC), restrictive cardiomyopathy clinical phenotypes which classically include dilated cardio- (RCM), and left ventricular noncompaction (LVNC). myopathy (DCM), hypertrophic cardiomyopathy (HCM), re- strictive cardiomyopathy (RCM), arrhythmogenic right ven- tricular cardiomyopathy (ARVC), left ventricular This article is part of the Topical Collection on Biomarkers of Heart Failure noncompaction (LVNC), and others (glycogen storage, mito- chondrial, conduction system, and ion channel disorders) * W. H. Wilson Tang [1–4]. [email protected] As genetic evaluation of cardiomyopathies is inherently complex and rapidly advancing, various consensus statements 1 Kaufman Center for Heart Failure, Department of Cardiovascular and guidelines have been published to assist medical practi- Medicine, Heart and Vascular Institute, Cleveland Clinic, tioners with the genetic evaluation of cardiomyopathies [5••, Cleveland, OH, USA 6••, 7]. Genetic evaluation framework of inherited cardiomy- 2 Division of Genetics and Genomics, MetroHealth Medical Center, opathies typically encompasses family history collection, ge- Cleveland, OH 44109, USA netic counseling, clinical screening of family members, and if 3 Center for Clinical Genomics, Cleveland Clinic, 9500 Euclid appropriate, molecular genetic testing. In this review, we sum- Avenue, Desk J3-4, Cleveland, OH 44195, USA marize the underlying genetics, practical considerations, Curr Heart Fail Rep guidelines’ recommendations, and evidence supporting the reminded that family history is insensitive to detect DCM genetic evaluation framework of these various hereditary and they should still undergo clinical screening [9]. It is also forms of primary cardiomyopathy. important to emphasize that a complete family history may demand repeated evaluation, occasionally requiring verifica- tion of primary sources of medical documentation from vari- DCM ous family members to confirm their accuracies. Genetics Molecular Genetic Testing The diagnosis of familial DCM is made when at least two closely related family members are affected by DCM, or in Genetic testing can be used to facilitate the establishment or the presence of a first-degree relative of a DCM patient, with confirmation of a diagnosis of familial DCM, especially in well-documented unexplained sudden death at ages 35 years cases with inconclusive family history. The recent develop- or younger [8, 9]. Clearly, these criteria have been arbitrarily ment of next-generation sequencing (NGS) methods has led to defined, and complete family history may not be readily avail- dramatic improvement in efficiency and speed of gene se- able in those with unexplained DCM. In clinical practice, quencing, as well as markedly reduced costs for clinical ge- DCM is more commonly encountered than other inherited netic testing [17, 18]. As a result, genetic testing for DCM is cardiomyopathies, but the familial component is less preva- becoming more widely available in the laboratories and more lent. Phenotype studies of DCM estimated that 20 to 48 % of commonly used in clinical practice. The lists of genes that can idiopathic DCM had a familial component [10–12], with au- lead to inherited cardiomyopathies and the testing laboratories tosomal dominant inheritance being the predominant pattern in the USA and worldwide are catalogued at the GeneTests of transmission, while X-linked, autosomal recessive, and mi- website funded by National Institutes of Health and the Ge- tochondrial inheritance being less common [13]. More than 40 netic Testing Registry of the National Center for Biotechnol- genetic mutations associated with DCM have been identified ogy Information website respectively [19, 20]. Due to signif- in familial DCM genetic studies (Table 1)[9]. These genes icant locus and allelic heterogeneity, the variant spectrum and encode components of a wide variety of cellular compart- detection rates of genetic testing for DCM are less well- ments and pathways, including the nuclear envelope, contrac- defined than those for HCM. The identification of variants tile apparatus, the force transduction apparatus (e.g., Z-disk of unknown clinical significance (VUS), wherein a genetic and costamere), gene transcription and splicing machinery, sequence variation is reported but the pathogenicity is un- and calcium handling [4, 16]. The variable phenotypic spec- known, limits its clinical utility particularly in the setting of trum of familial DCM is possibly attributed to incomplete predictive testing as asymptomatic at-risk family members penetrance, the presence of modifier genes, age-related pene- should not be tested for these types of variants. It is estimated trance, and/or variable expressivity of the genetic mutations that the DCM genetic testing sensitivity now ranges from 15 [9]. The recently discovered titin gene (TTN) is a good exam- to 25 % [9]. ple of the clinical variability of the various mutations, where- by location and type of mutation in the gene can result in different degrees of functional alterations. Genetic Counseling Family History Genetic counseling is an integral part of the DCM genetic testing process and has been recommended in major Family history remains an essential component in the evalua- guidelines [6••, 7]. Genetic counseling sessions, common- tion of DCM, with the goals of ascertaining if the DCM may ly conducted by genetic counselors or medical geneticists, be familial, determining the inheritance pattern, and to identify is of paramount importance in providing an explanation of family members who may be at risk [6••, 7]. A careful family the benefits, risks, and limitations of clinical and/or ge- history for three or more generations, including history of netic testing for patients with familial DCM and their at- heart failure, DCM, cardiac transplantation, unexplained sud- risk relatives. It also includes a review of the characteris- den death, unexplained cardiac conduction system disease tics and genetics of familial DCM, a thorough pedigree and/or arrhythmia, or unexplained stroke or other thromboem- analysis to ascertain the likely pattern of inheritance, and bolic disease should be obtained to assess the possibility of advice to assist families in making psychosocial adjust- familial DCM. With a suggestive family history for familial ments to the recognition of a potentially heritable disorder DCM, medical records or death certificates of the affected in the family [21]. In fact, many insurance companies family members should be requested to verify the diagnosis. require pretest genetic counseling in order for the testing If family history is negative, family members should be to be covered. Curr Heart Fail Rep Table 1 Genetic mutations associated with cardiomyopathies Gene symbol Gene name DCM HCM ARVC RCM LVNC Inheritance pattern ABCC9 ATP-binding cassette, subfamily C, member 9 X AD ACTC α-Cardiac actin XX X X AD ACTN2 α-Actinin2 XX AD ANKRD1 Cardiac ankyrin repeat, domain 1 XX Unknown BAG3 BCL2-associated athanogene 3 X X AD CASQ2 Cardiac calsequestrin 2 X AR CAV3 Caveolin 3 X AD, AR COX15 COX 15 homolog, cytochrome C oxidase assembly protein X AR CRYAB Crystallin αB X AD, AR CSRP3 Cysteine and glycine-rich protein 3 XX AD CTF1