Whole mitochondrial genome sequencing of Malaysian patients with cardiomyopathy

Abstract

Cardiomyopathy (CMP) constitutes a diverse group of myocardium diseases affecting the pumping ability of the heart. Genetic predisposition is among the major factors affecting the development of CMP. Globally, there are over 100 genes in autosomal and mitochondrial DNA (mtDNA) that have been reported to be associated with the pathogenesis of CMP. However, most of the genetic studies have been conducted in Western countries, with limited data being available for the Asian population. Therefore, this study aims to investigate the mutation spectrum in the mitochondrial genome of 145 CMP patients in Malaysia. Long-range PCR was employed to amplify the entire mtDNA, and whole mitochondrial genome sequencing was conducted on the MiSeq platform. Raw data was quality checked, mapped, and aligned to the revised Cambridge Reference Sequence (rCRS). Variants were named, annotated, and filtered. The sequencing revealed 1,077 variants, including 18 novel and 17 CMP and/or mitochondrial disease-associated variants after filtering. In-silico predictions suggested that three of the novel variants (m.8573G>C, m.11916T>A and m.11918T>G) in this study are potentially pathogenic. Two confirmed pathogenic variants (m.1555A>G and m.11778G>A) were also found in the CMP patients. The findings of this study shed light on the distribution of mitochondrial mutations in Malaysian CMP patients. Further functional studies are required to elucidate the role of these variants in the development of CMP.

Whole genome sequencing in paediatric channelopathy and cardiomyopathy

“…Mutation in the TAFAZZIN gene (NM_000116.5):c.284+5G>A in patient 1-two aberrant splicing events occur in proband, resulting in a 106 bp and another 87 bp intron retention, with an immature stop codon created at the start of intron 3. (28)(29)(30). Therefore, the variant is classified as pathogenic (PVS1, PM2_supporting, PM3).…”

Mitochondrial dysfunction in the pathogenesis of hypertrophic cardiomyopathy

“…Несмотря на то, что митохондриальная дисфункция вовлечена в патоморфогенез ГКМП, мутации генов митохондриальных белков изучены не так хорошо, как мутации белков саркомера. Обнаружение мутаций митохондриальной ДНК (мтДНК) у пациентов с ГКМП является сложной задачей в связи с наличием феномена гетероплазмии и вариабельности их фенотипического выражения [52,53]. У пациентов с ГКМП, ассоциированной с мутациями мтДНК, может наблюдаться ряд клинических особенностей, включая гипертрофию миокарда, аритмии, сердечную недостаточность и другие сердечно-сосудистые нарушения [54].…”