Dilated cardiomyopathy

Clinical features

Cardiomyopathies are disorders with primary abnormalities in the structure and function of the heart. These disorders are commonly grouped into morphological subtypes which include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and left ventricular noncompaction cardiomyopathy (LVNC) ¹.

Dilated cardiomyopathy is defined by the presence of left ventricular dilatation and resulting contractile dysfunction. Genetic mutations involving genes that encode cytoskeletal, sarcomere, and nuclear envelope proteins, among others, account for up to 35% of dilated cardiomyopathy cases¹. Idiopathic dilated cardiomyopathy has become one of the most prevalent inherited cardiomyopathies over the past decades. Genetic screening of first-degree relatives has revealed that 30-50% of the cases have a familial origin ². The prevalence of DCM is estimated at 1:250 ³.

Dilated cardiomyopathy (DCM) may be asymptomatic for a number of years. Presentation usually occurs late in the disease course with any one of the following:

• Heart failure, characterized by symptoms that include edema, orthopnea, paroxysmal nocturnal dyspnea, fatigue and dyspnea on exertion
• Arrhythmias and/or conduction system disease symptoms that almost exclusively accompany progressive cardiomyopathy and heart failure
• Thromboembolic disease, including stroke or systemic embolus, and secondary to left ventricular mural thrombus.

More than 50% of DCM-affected cases are genetically determined, and so far more than 40 genes have been identified affecting proteins of a wide variety of cellular structures that regulate cardiac muscle function, such as the sarcomere, the nuclear envelope, the cytoskeleton, the sarcolemma and the intercellular junction⁴.

A range of approximately 10-20% of DCM, regardless of family history, has been attributed to pathogenic truncating variants in the TTN gene, encoding for protein tintin^{4, 5}. Titin is the largest-known human protein, highly expressed in the sarcomere of the heart muscle. TTN provides both passive force and elasticity to preserve diastolic and systolic function. Also, titin regulates the assembly and length of the sarcomere. While the role of truncation mutations in DCM is accepted, the pathogenic and prognostic role of missense variants is still debated and under investigation.

One of the most commons genes implicated in familial DCM is LMNA, encoding the intermediate filament proteins lamin A. LMNA mutations account for 6% of familial DCM cases^{1, 6, 7}. LMNA gene mutations may be associated with extracardiac features, including skeletal muscle weakness and contractures in the form of Emery-Dreifuss muscular dystrophy or limb girdle muscular dystrophy type. LMNA mutations can also produce Hutchinson-Guilford progeria syndrome, lipodystrophy, and Charcot-Marie-Tooth syndrome type 2B. Cardiovascular disease with LMNA mutations can be limited to DCM with or without conduction system disease.

Mutations in the sarcomere genes cause both hypertrophic cardiomyopathy (HCM) and DCM. Sarcomere mutations have been identified in 25% of idiopathic DCM cases1 and account for 10% of familial DCM^{1, 7}. The most common sarcomere genes identified in familial DCM are β-myosin heavy chain (MYH7) (~4%)^{1, 7} and Troponin T (TNNT2) (2.9%)^{1, 7}. Other sarcomere genes identified in familial DCM are α-tropomyosin (TPM1), troponin C (TNNC1), troponin I (TNNI3), cardiac actin (ACTC), and others. Furthermore, an analysis of Becker muscular dystrophy gene mutations has indicated the regions of the dystrophin protein that may be prone to cardiomyopathy⁷. Additional genes which act as part of calcium regulation and ion channels have been identified as causative of DCM.

Treatment of dilated cardiomyopathy and resulting chronic heart failure includes medications that improve survival, such as angiotensin converting enzyme inhibitors (ACE) and β blockers⁸, and must be used as a preventive measure. Other interventions include arrhythmia management using device therapy and sudden death prevention. Patients who are refractory to medical therapy might benefit from mechanical circulatory support and heart transplantation. Treatment of preclinical disease and the potential role of stem-cell therapy are being investigated⁸.

CENTOGENE offers full gene sequencing in the Cardiomyopathy dilated panel (genes: ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CRYAB, CSRP3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, EMD, EYA4, FKTN, GATA4, GATAD1, ILK, LAMA4, LAMP2, LDB3, LMNA, MURC, MYBPC3, MYH6, MYH7, MYPN, NEBL, NEXN, PDLIM3, PKP2, PLN, PRDM16, RAF1, RBM20, SCN5A, SGCD, TAZ, TBX20, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, TXNRD2, VCL) and deletion/duplication test of selected genes from the panel: MYBPC3, TNNT2, SGCD, MYH7, RAF1, BAG3, DMD, DSC2, DSG2, SCN5A, LMNA, PKP2, FKTN, DSP, GATA4).

The differential diagnosis of dilated cardiomyopathy related disorders – depending on the major symptoms in the initial case – includes the following diseases¹:

• HFE-associated hereditary hemochromatosis
• Emery-Dreifuss muscular dystrophy
• Limb girdle muscular dystrophy 1B
• Laing distal myopathy
• Carvajal syndrome
• Becker muscular dystrophy (late onset of dilated cardiomyopathy)
• Barth syndrome

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for dilated cardiomyopathy NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Cardiomyopathy dilated panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Cardiomyopathy dilated panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

The following individuals are candidates for dilated cardiomyopathy panel genetic testing:

• Individuals with a family history of disease and presentation of the most common symptoms
• Individuals without a positive family history, but with symptoms resembling this disease
• Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s panel for dilated cardiomyopathy can be found in our genetic test catalogue.