TABLE 1.
Principal pathogenic gene mutations described in genetic DCM along with their clinical and cellular phenotype.
| Gene | Prevalence | Clinical phenotype | #hiPSC studies (References) | Functional output |
| Titin (TTN) | 19–25% of familial forms 11–18% of sporadic forms | Usually milder forms of DCM, with LV reverse remodeling described after OMT. Can be associated with tibial muscle dystrophy and HCM (McNally and Mestroni, 2017). Truncating variants are related to alterations in mitochondrial function, increased interstitial fibrosis and reduced hypertrophy, along with increased ventricular arrhythmias at long-term follow-up, with a similar survival and overall cardiac function with respect to idiopathic DCM (Verdonschot et al., 2018). | 5 (Hinson et al., 2015; Streckfuss-Bomeke et al., 2017; Chopra et al., 2018; Schick et al., 2018; Zaunbrecher et al., 2019) | Contractile deficit |
| Lamin A/C (LMNA) | 5–6% of genetic DCM | Malignant DCM characterized by young onset, high penetrance, dysrhythmias (sinus node dysfunction, AF, atrioventricular node dysfunction, VT, VF, SCD), LV dysfunction and HF with reduced survival and frequent need for HT. Cardiac conduction system disease usually precedes the development of LV dilation and dysfunction (Hasselberg et al., 2018). | 6 (Siu et al., 2012; Wyles et al., 2016a; Lee et al., 2017; Bertero et al., 2019; Salvarani et al., 2019; Shah et al., 2019) | LMNA haploinsufficieny; conduction defects; contractile defects |
| β-Myosin heavy chain (MYH7) | 3–4% of DCM | Sarcomeric rare variant carriers show a more rapid progression toward death or HT compared to non-carriers, particularly after 50 years of age (Merlo et al., 2013). | ? | |
| Cardiac troponin T (TNNT2) | 3% of DCM | Clinical and prognostic profiles depend on type of mutation: carriers of Arg92Gln mutation have a worse prognosis than those with other mutations in TNNT2 or other sarcomeric genes (Ripoll-Vera et al., 2016). | 6 (Sun et al., 2012; Wu et al., 2015; Broughton et al., 2016; Burridge et al., 2016; Wang L. et al., 2018; Shafaattalab et al., 2019) | Calcium handling abnormalities; contractile defects |
| Type V voltage-gated cardiac Na channel (SCN5A) |
2–3% of DCM | Arrhythmias (commonly AF) and myocyte dysfunction leading to progressive deterioration of LV systolic function (Bondue et al., 2018). Overlapping phenotypes: LQT, Brugada. | 1 (Moreau et al., 2018) | Electrophysiological defects; Arrhythmias |
| RNA-binding protein 20 (RBM20) | 1–5% of DCM | Malignant arrhythmic phenotype with high frequency of AF and progressive HF (Ripoll-Vera et al., 2016). | 3 (Wyles et al., 2016a, b; Streckfuss-Bomeke et al., 2017) | Calcium handling abnormalities; contractile defects |
| Desmoplakin (DSP) | 2% of DCM | Associated with Carvajal syndrome (autosomal recessive genetic disorder characterized by woolly hair, striate palmoplantar keratoderma and DCM). Additional phenotypic signs: dental abnormalities and leukonychia. LV dilatation usually asymptomatic at an early age. DCM progresses rapidly, leading to HF or SCD in adolescence (Yermakovich et al., 2018). | 1 (Ng et al., 2019) | ACM |
| Dystrophin (DMD, Xp21.1 locus 16) | <2% of genetic DCM | Associated with Duchenne and Becker muscular dystrophy. Severe cardiac involvement in Duchenne (milder and later onset in Becker muscular dystrophy) with supraventricular arrhythmias, atrio-ventricular blocks and right bundle branch block, progressive LV dysfunction and HF (Mestroni et al., 2014). | 20 (Dick et al., 2013; Guan et al., 2014; Zatti et al., 2014; Lin et al., 2015; Macadangdang et al., 2015; Japp et al., 2016; Nanni et al., 2016; Young et al., 2016; Kyrychenko et al., 2017; Zhang et al., 2017; Long et al., 2018; Caluori et al., 2019; Eisen et al., 2019; Farini et al., 2019; Jelinkova et al., 2019; Min et al., 2019; Pioner et al., 2019a; Sato et al., 2019; Tsurumi et al., 2019; Moretti et al., 2020) | Calcium handling abnormalities; contractile defects |
| α-Tropomyosin (TPM1) | 1–2% of DCM | Overlapping phenotypes: LVNC, HCM (McNally and Mestroni, 2017) | 1 (Takasaki et al., 2018) | Sarcomere defects |
| Desmin (DES) | 1–2% of DCM (Taylor et al., 2007) | Malignant phenotype associated with desminopathies and myofibrillar myopathy. Can cause a spectrum of phenotypes from skeletal myopathy, mixed skeletal–cardiac disease (“desmin-related myopathy”), and cardiomyopathy (DCM as well as HCM or RCM). DCM is typically preceded by skeletal myopathy and can be associated with conduction defects (Mestroni et al., 2014). | 1 (Tse et al., 2013) | DES protein aggregates |
| Filamin C (FLNC) | 1% of DCM | Cardiomyopathy associated with myofibrillar myopathy and LVNC; high rate of ventricular arrhythmias and SCD (particularly in truncating variants) (Ader et al., 2019). | ? | |
| Metavinculin (VCL) | 1% of DCM | Can cause either DCM or HCM phenotype (Vasile et al., 2006) | ? | |
| Phospholamban (PLN) | Rare (except for Netherlands where prevalence reaches 15% of DCM due to R14del mutation with founder effect) (van der Zwaag et al., 2012) | Early onset DCM with lethal ventricular arrhythmias. Low QRS complex potentials and decreased R wave amplitude, negative T waves in left precordial leads (Hof et al., 2019). PLN R14del mutation associated with high risk for malignant arrhythmias and end-stage HF from late adolescence, can cause either a DCM phenotype or ARVC (Mestroni et al., 2014). A milder phenotype is also reported (DeWitt et al., 2006). |
4 (Karakikes et al., 2015; Stillitano et al., 2016; Ceholski et al., 2018; Stroik et al., 2019) | Electrophysiological defects |
| α-/β-/δ-Sarcoglycan (SGCA, SGCB, SGCD) | Rare | Recessive mutations in δ-sarcoglycan linked to limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan linked to DCM (Campbell et al., 2016). | ? | Ca handling abnormalities; Contractile defects |
| α-cardiac actin (ACTC1) | Rare | Familial atrial septal defect combined with a late-onset DCM (Frank et al., 2019). Can be associated with HCM and LVNC | ? | |
| Cardiac troponin I (TNNI3) | Rare | Overlapping phenotype: HCM (McNally and Mestroni, 2017). | 1 (Chang et al., 2018) | Telomere shortening |
| Cardiac troponin C (TNNC1) | Rare | Overlapping phenotypes: LVNC, HCM (McNally and Mestroni, 2017). | ? | |
| Troponin I–interacting kinase (TNNI3K) | Rare | Conduction defect, AF (McNally and Mestroni, 2017). | ? | |
| α-actinin 2 (ACTN2) | Rare | Overlapping phenotype: LVNC (McNally and Mestroni, 2017). | ? | |
| BCL2-associated athanogene 3 (BAG3) | Rare | Associated with myofibrillar myopathy (McNally and Mestroni, 2017). | 1 (Judge et al., 2017) | Disrupted myofibril; Contractile deficit |
| α-B-crystallin (CRYAB) | Rare | Associated with protein aggregation myopathy (McNally and Mestroni, 2017). | 1 (Mitzelfelt et al., 2016) | Protein Aggregates; cellular stress |
| Titin-cap/telethonin (TCAP) | Rare | Associated with limb-girdle muscular dystrophy (McNally and Mestroni, 2017). | ? | |
| Muscle LIM protein (CSRP3) | Rare | Overlapping phenotype: HCM (McNally and Mestroni, 2017). | 1 (Li et al., 2019) | Calcium handling abnormalities |
| Cardiac ankyrin repeat protein (ANKRD1) | Rare | Associated with congenital heart disease (McNally and Mestroni, 2017). | ? | |
| Cipher/ZASP (LDB3) | Rare | Overlapping phenotype: LVNC (McNally and Mestroni, 2017). | ? | |
| Nebulette (NEBL) | Rare | Overlapping phenotypes: LVNC, HCM (McNally and Mestroni, 2017). | ? | |
| Emerin (EMD) | Rare | Associated with Emery–Dreifuss muscular dystrophy (McNally and Mestroni, 2017). | 1 (Shimojima et al., 2017) | Calcium handling abnormalities |
| Sulfonylurea receptor 2A, component of ATP-sensitive potassium channel (ABCC9) | Rare | Associated with AF, Osteochondrodysplasia (McNally and Mestroni, 2017). | ? | |
| Potassium channel (KCNQ1) | Rare | Associated with AF, LQT1, short QT1, Jervell and Lange-Nielsen syndrome (McNally and Mestroni, 2017). | ? | |
| HSP40 homolog, C19 (DNAJC19) | Rare | Associated with 3-methylglutaconic aciduria, type V (McNally and Mestroni, 2017). | 1 (Rohani et al., 2020) | Mitochondrial abnormalities |
| Tafazzin (TAZ/G4.5) | Rare | Associated with LVNC, Barth syndrome, endocardial fibroelastosis 2 (McNally and Mestroni, 2017). | 1 (Wang et al., 2014) | Mitochondrial defects; contractile defects |