Role of genetic testing in cardiomyopathies: Α primer for cardiologists

Table 1 Terminology of commonly used genetics vocabulary

Term	Definition
Allele	One of several alternative versions of a particular gene
Heterozygote	An individual who has different alleles at a particular gene locus on homologous chromosomes (carrier of a single copy of the mutation)
Mutation	Any alteration in the inherited nucleic acid sequence of the genotype of an organism; a mutation considered in the context of a genetic disease usually refers to an alteration that causes a Mendelian disease
Penetrance	Proportion of individuals carrying a mutation who also express a cardiomyopathy phenotype
Genome sequencing	Sequencing of entire genome (coding and non-coding regions)
Exome sequencing	Sequencing of the coding regions (exons)
Proband or index case	Index case in the family, usually the one with the most severe phonotype
Variant	A change in the DNA sequence which may or may not be disease-causing
Pathogenicity	Process of determining whether a variant is causative or not

Table 2 Prevalence, inheritance pattern, genes and indications for genetic testing involved in specific cardiomyopathies

Inherited CMP	Prevalence	Pattern of inheritance	Key genes	Diagnostic yield of genetic testing	Recommendation for genetic testing
HCM	1 in 500	AD	MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3, GLA, PRKAG2, LAMP2	30%-60%	For any patient with clinical diagnosis of HCM; Familial screening with a mutation after identified in the index case
DCM	1 in 2500	AD, X-linked	DES, DMD, DSP, FLNC, LMNA, MYH7, PLN, RBM20, TNNI3, TNNT2, TTN, TPM1	20%-30%	For patients with DCM and conduction disease and/or family history of SCD; Familial screening with a mutation after identified in the index case
ARVC	1 in 2000-5000	AD, AR	DSC2, DSG2, DSP, JUP, PLN, TMEM43	50%	Familial screening with a mutation after identified in the index case
RCM	Rare	AD, AR X-linked or mitochondrial	Troponin; MYBPC3, MYL3	Unknown	Familial screening with a mutation after identified in the index case

ARVC: Arrhythmogenic right ventricular cardiomyopathy; DCM: Dilative cardiomyopathy; HCM: Hypertrophic cardiomyopathy; RCM: Restrictive cardiomyopathy; AD: Autosomal dominant; AR: Autosomal recessive; MYH7: β-myosin heavy chain; MYBPC3: Myosin-binding protein C3; TNNI3: Troponin I3; TNNT2: Troponin T2; TPM1: Tropomyosin; ACTC1: Actin alpha cardiac muscle 1; MYL2: Myosin light chain 2; MYL3: Myosin light protein; GLA: Alpha-galactosidase; PRKAG2: Protein kinase AMP-activated non-catalytic subunit gamma 2; LAMP2: Lysosomal-associated membrane protein; DES: Desmin; DMD: Dystrophin; DSP: Desmoplakin; FLNC: Filamin C; LMNA: Lamin A/C; PLN: Phospholamban; DSC2: Desmocollin 2; DSG2: Desmoglein 2; JUP: Junction plakoglobin; RBM20: RNA-binding protein 20; SCD: Sudden cardiac death; TMEM43: Transmembrane protein 43; 2; TTN: Titin.

Table 3 Definitions of the variant classifications

Variant	Definition
Pathogenic	Variant is disease-causing with > 99% confidence; Cascade genetic testing should be offered to family members
Likely pathogenic	Variant is disease-causing with > 90%-95% confidence; Cascade genetic testing should be offered to family members
VUS	Variant is considered uncertain with an unknown effect on clinical phenotype, as there is insufficient or conflicting evidence for pathogenicity; Cascade genetic testing cannot be offered to family members
Likely benign	Variant is probably not disease-causing; Cascade genetic testing should not be offered to family members
Benign	Variant is not disease-causing; Cascade genetic testing should be offered to family members

VUS: Variant of uncertain significance.