Genotype-Phenotype Correlations in Dilated Cardiomyopathy

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Cardiomyopathies are heart diseases, which are categorized according to morphology and function into hypertrophic, dilated, restrictive and arrhythmogenic right ventricular subtypes with significant genetic and phenotypic overlap. Dilated cardiomyopathy (DCM) is a heart disease characterized by left ventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause the phenotype. The diagnosis is based on echocardiography or other imaging modalities. The prevalence of DCM is estimated to be at least 1:2500. The proportion of familial or genetic DCM is currently estimated to be 30-50%. The mode of inheritance is typically autosomal dominant, but other inheritance patterns have been identified. Over 40 genes have been related to DCM, and about a hundred to cardiomyopathies in general, which is why the genetic etiology has often remained unknown. Next generation sequencing methods allow the sequencing of all known cardiomyopathy-related genes simultaneously. Thus, many DCM patients without a genetic diagnosis are now receiving one. Dilated cardiomyopathy is not a homogeneous disease entity, and some genetic causes produce a distinct phenotype. These genotype-phenotype correlations can help to identify familial disease, lead to successful genetic testing and guide clinical decision-making. The aims of this thesis were the identification of new cardiomyopathy-causing variants, and the description of genotype-phenotype correlations in dilated cardiomyopathy. LMNA mutations are the second most common cause of genetic dilated cardiomyopathy. In this thesis new LMNA mutations were reported, and LMNA mutation carriers were studied in detail to further analyse the phenotype. In study I four cardiomyopathy-causing LMNA variants were identified. One of the mutations was studied in more detail due to its atypical phenotype affecting primarily the right side of the heart. In study II 26 individuals carrying DCM-causing LMNA-mutations were studied repeatedly using spiroergometry. The symptomatic mutation carriers showed changes seen typically in heart failure patients. The findings of the asymptomatic mutation carriers concerning maximal working capacity and oxygen uptake were similar to those of healthy controls. However, the asymptomatic mutation carriers showed also signs of inefficient ventilation during incremental exercise, which might signify evolving cardiomyopathy. In study III clinical follow-up results of 27 LMNA mutation carriers were reported and a new ECG entity, septal remodeling, common in LMNA mutation carriers and rare in other cardiomyopathy patients was introduced. In the clinical follow-up men exhibited cardiomyopathy symptoms earlier than females. Due to rigorous follow-up a very high non-sustained ventricular tachycardia (NSVT) prevalence, 77.8%, was found in LMNA mutation carriers highlighting the need for accurate risk-assessment schemes for clinical decision-making concerning ICD implantation. In study IV a targeted sequencing panel using Os-Seq technology and covering 101 genes associated with cardiomyopathy was used to study 145 Finnish DCM patients. Study IV confirmed the significance of truncating titin variants as the most significant known cause for DCM. Truncating titin variants were found in 20.6% of familial DCM patients and 14.6% of non-familial DCM patients. The overall diagnostic yields were 47.6% for patients with familial disease and 25.6% for those without a family history of cardiomyopathy.

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