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

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.

The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice

“…Numerous human mutations in mitochondrial assembly factors have been shown to contribute to respiratory chain dysfunction and disease ( 54 ), and given that there are currently many clinical cases of mitochondrial deficiency with no known genetic cause, it is possible that a subset of these may be due to mutations in microprotein assembly factors that have yet to be discovered. Mitochondrial defects are also a common cause of pediatric cardiomyopathy ( 55 , 56 ), and cardiac dysfunction is frequent in children with mitochondrial disease and is associated with increased mortality ( 57 ). This area of investigation is still poorly understood, and the genetic risk factors associated with these diseases have yet to be fully elucidated ( 58 ), suggesting that defects in newly identified or currently unknown microproteins may be contributing factors.…”

Case report: Rare novel MIPEP compound heterozygous variants presenting with hypertrophic cardiomyopathy, severe lactic acidosis and hypotonia in a Chinese infant

“…Mitochondrial diseases (MDs) are rare, with a prevalence of 5–12/100,000 ( 1 ). They are characterized by oxidative phosphorylation (OXPHOS) dysfunction caused by nuclear and/or mitochondrial DNA (mtDNA) variations ( 2 – 4 ).…”

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

“…Most previously reported genes are commonly included in diagnostic tests. Moreover, in recent years, advances in high-throughput sequencing strategies, such as next-generation sequencing (NGS), have revolutionized the diagnosis of inherited heart diseases in terms of expanding the number of involved genes and the discovery of new genes potentially associated with the diseases [ 5 , 53 , 54 , 55 , 56 , 57 ].…”