Hereditary Cardiomyopathies

The World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies define cardiomyopathies as a group of diseases of the myocardium that result in cardiac dysfunction. Although cardiomyopathy may be secondary to myocardial damage (e.g., myocardial infarction or hypertension), this chapter discusses the genetic basis of intrinsic cardiomyopathies without other identifiable causes.

Cardiomyopathies are classically divided into several categories based on anatomic and physiological properties: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC). Each of these are associated with genetic mutations ( Table 32.1 to Table 32.3 ).

TABLE 32.1

Gene Defects Associated With Dilated Cardiomyopathy

Gene	Protein	Cardiac Features	Extracardiac Features	Inheritance
Abnormalities of Force Production
MYH7	β-myosin heavy chain	Early-onset LV dilation Also causes HCM		AD
ACTC	Actin	Also causes HCM		AD
TNNI3	Troponin I	Also causes HCM		AD
TNNT2	Troponin T	Early onset LV dilation Also causes HCM		AD
TNNC1	Troponin C			AD
TPM1	α-tropomyosin	Also causes HCM		AD
Abnormalities of Force Transduction
TTN	Titin	Also causes HCM Associated with peripartum cardiomyopathy		Mixed
DES	Desmin	Syncope	Skeletal myopathy	AD, AR
DMD	Dystrophin	Rapid progression to end-stage heart failure	Duchenne muscular dystrophy Becker muscular dystrophy	XR
SGCD	δ-sarcoglycan	Sudden death	Limb-girdle-muscular dystrophy (2F)	AR
Nuclear Proteins
LMNA	Lamin A/C	Conduction abnormalities Sudden death Also associated with HCM, RCM, LVNC	Muscular dystrophy, Charcot-Marie tooth disease	AD
Other
PLN	Phospholamban (reversible inhibitor of SERCA)	Progresses to end-stage HF in mid-life, requiring cardiac transplantation		AD
TAZ	Tafazzin	Endocardial fibroelastosis, associated with LVNC	Barth syndrome	XR
EYA4	EYA protein		Sensorineural hearing loss	AD

AD , Autosomal dominant; AR , autosomal recessive; HCM , hypertrophic cardiomyopathy; HF , heart failure; LV , left ventricle; LVNC , LV noncompaction cardiomyopathy; RCM , restrictive cardiomyopathy; XR , X-linked recessive.

TABLE 32.2

Gene Defects Associated With Hypertrophic Cardiomyopathy

Gene	Protein	Features	Inheritance
Thick-Filament Proteins
MYH7	β-myosin heavy chain	High risk of sudden death	AD
MYL1	Myosin light chain-1	Papillary muscle thickening	AD
MYL2	Myosin light chain-2	Papillary muscle thickening	AD
Thin-Filament Proteins
TNNT2	Troponin T	High risk of sudden death	AD
TNNI3	Troponin I	High risk of sudden death	AD
ACTC	Actin	Also causes DCM	AD
TPM1	α-tropomyosin	High risk of sudden death May progress from HCM to DCM	AD
MYBPC3	Myosin binding protein C	Mild presentation, later onset	AD
Lysosomal Protein
LAMP2	Lysosome-associated membrane protein	Danon disease with skeletal, neurological, and hepatic involvement WPW Males often end-stage disease by second decade of life	XR
GLA	Lysosomal hydrolase α-galactosidase A protein	Cardiac Fabry disease Enzyme replacement therapy (α-galactosidase A)	XR
Glycogen Storage Cardiomyopathy
PRKAG2	Gamma ₂ regulatory subunit of AMP activated protein kinase	Atrioventricular block Atrial fibrillation WPW	AD

AD , Autosomal dominant; AMP , adenosine monophosphate; AR , autosomal recessive; DCM , dilated cardiomyopathy; RCM , restrictive cardiomyopathy; WPW , Wolff-Parkinson-White; XR , X-linked recessive.

TABLE 32.3

Gene Defects Associated With Arrhythmogenic Right Ventricular Cardiomyopathy

Gene	Protein	Features	Inheritance
PKP2	Plakophilin 2	Common mutation	AD
DSG2	Desmoglein 2	Common mutation	AD
JUP	Junctional plakoglobin	Associated with Naxos disease	AR
DSP	Desmoplakin	Associated with Naxos disease	AR
RYR2	Ryanodine receptor	Ryanodine receptor is also associated with catecholaminergic polymorphic VT	AD
DSC2	Desmocollin-2		AD

AD , Autosomal dominant; AR , autosomal recessive; VT , ventricular tachycardia.

Although genetic mutations can occur in familial or hereditary patterns, it is important to recognize that they can occur de novo, in the absence of family history of cardiomyopathy. In addition, familial cardiomyopathies can occur in the absence of an identifiable genetic mutation, because knowledge of genetics is expanding with newer technologies, such as next-generation sequencing. In this chapter, the term hereditary cardiomyopathy refers to all genetic cardiomyopathies, independent of familial history.

Genetic mutations may also be associated with multiple types of cardiomyopathies or arrhythmic disease. As examples, mutations of MHY7 (β-myosin heavy chain) are associated with both HCM and DCM, and mutations in SCN5A (sodium ion channel) are associated with both DCM and arrhythmias. There is also increasing recognition of a genetic influence in cardiomyopathies that are not classically considered to be genetic or hereditary. For example, genetic testing of women with peripartum cardiomyopathy revealed that 15% of them had genetic mutations. Finally, genetic mutations can be associated with syndromes that involve extracardiac findings (see Table 32.1 ).

Etiology and Pathogenesis

Dilated Cardiomyopathy

Patients with DCM develop eccentric cardiac remodeling, left and right ventricular dysfunction, heart failure, and arrhythmias. More than 50 mutations have been implicated in DCM, and approximately 35% of patients with familial DCM have an identifiable mutation. The most common affected genes are titin (TTN) , lamin A/C (LMNA) , β-myosin heavy chain (MYH7) , and cardiac troponin T (TNNT) . Mutations can be subcategorized by their histology and role in cardiac function ( Fig. 32.1 and see Table 32.1 )

FIG 32.1, Interaction of Affected Proteins.

Abnormalities of Force Production

Mutations in genes that code for sarcomeric proteins affect force production and transmission. Common mutations involve genes that code actin (ACTC) , β-myosin heavy chain (MYH7) , troponin (TNNI3 , TNNT2 , TNNC1) , and α-tropomyosin (TPM1) . Early-onset ventricular dilation and dysfunction are common. These genes are also associated with HCM. Inheritance is predominantly autosomal dominant, although incomplete penetrance is common.

Abnormalities of Force Transduction

Multiple mutations affect Z-disk interacting proteins that mediate detection and modulation of mechanical stress. Common mutations include desmin (DES) , dystrophin (DMD) , δ-sarcoglycan (SGCD) , and titin (TTN) . TTN is a giant protein that extends from the Z disk to the M-line of the sarcomere, acting as a spring that regulates passive tension and active contraction. Due to its immense size, its role in DCM was a technical barrier for years. However, with next-generation sequencing, TTN truncations can now be identified in 25% of cohorts of familial DCM. Extracardiac muscular dystrophies are also implicated in mutations of DMD (Duchenne and Becker muscular dystrophy) and SGCD (limb-girdle-muscular dystrophy).

Nuclear Proteins

Mutations that cause cardiomyopathy also occur in nuclear proteins, including LMNA , thymopoietin (TMPO) , and CARP (ANKRD1) . LMNA mutations result in a well-recognized genetic abnormality with several extracardiac phenotypes (muscular dystrophies, Charcot-Marie tooth disease) and a variety of cardiac phenotypes (including atrial fibrillation, DCM, RCM, and HCM). Notably, LMNA mutations are associated with progressive conduction abnormalities and high risk of sudden death and shocks from implantable cardiac-defibrillators (ICDs).

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