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Review
. 2021 May 27;22(11):5742.
doi: 10.3390/ijms22115742.

Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes

Cristina Mazzaccara  1   2 , Bruno Mirra  1   2 , Ferdinando Barretta  1   2 , Martina Caiazza  3   4 , Barbara Lombardo  1   2 , Olga Scudiero  1   2 , Nadia Tinto  1   2 , Giuseppe Limongelli  3   4 , Giulia Frisso  1   2
Affiliations
Review

Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes

Cristina Mazzaccara et al. Int J Mol Sci. .

Abstract

Mitochondrial Cardiomyopathy (MCM) is a common manifestation of multi-organ Mitochondrial Diseases (MDs), occasionally present in non-syndromic cases. Diagnosis of MCM is complex because of wide clinical and genetic heterogeneity and requires medical, laboratory, and neuroimaging investigations. Currently, the molecular screening for MCM is fundamental part of MDs management and allows achieving the definitive diagnosis. In this article, we review the current genetic knowledge associated with MDs, focusing on diagnosis of MCM and MDs showing cardiac involvement. We searched for publications on mitochondrial and nuclear genes involved in MCM, mainly focusing on genetic screening based on targeted gene panels for the molecular diagnosis of the MCM, by using Next Generation Sequencing. Here we report twelve case reports, four case-control studies, eleven retrospective studies, and two prospective studies, for a total of twenty-nine papers concerning the evaluation of cardiac manifestations in mitochondrial diseases. From the analysis of published causal mutations, we identified 130 genes to be associated with mitochondrial heart diseases. A large proportion of these genes (34.3%) encode for key proteins involved in the oxidative phosphorylation system (OXPHOS), either as directly OXPHOS subunits (22.8%), and as OXPHOS assembly factors (11.5%). Mutations in several mitochondrial tRNA genes have been also reported in multi-organ or isolated MCM (15.3%). This review highlights the main disease-genes, identified by extensive genetic analysis, which could be included as target genes in next generation panels for the molecular diagnosis of patients with clinical suspect of mitochondrial cardiomyopathies.

Keywords: diagnosis; genetic testing; mitochondrial DNA; mitochondrial cardiomyopathy; mitochondrial disease; mutation; next generation sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Rates of protein functions and RNA involved in mitochondrial cardiomyopathies. The figure groups all the 130 genes, reported in Table 3 associated with mitochondrial heart disease, according to their function. A large proportion of these genes (34.3%) encode for key proteins in oxidative phosphorylation system, either as directly OXPHOS subunits (22.8%) and as OXPHOS assembly factors (11.5%). Furthermore, mutations in several mitochondrial tRNA genes have been reported with multi-organ or isolated MCM (15.3%). Mainly HCM, but also DCM or histiocytoid cardiomyopathy, are the main cardiomyopathies associated with pathogenic variants in genes encoding mitochondrial tRNAs. Mutations in mt-tRNA may damage overall mitochondrial translation by alteration of functional mt-tRNAs.
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