Private Mitochondrial DNA Variants in Danish Patients with Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease primarily caused by mutations in genes coding for sarcomeric proteins. A molecular-genetic etiology can be established in ~60% of cases. Evolutionarily conserved mitochondrial DNA (mtDNA) haplogroups are susceptibility factors for HCM. Several polymorphic mtDNA variants are associated with a variety of late-onset degenerative diseases and affect mitochondrial function. We examined the role of private, non-haplogroup associated, mitochondrial variants in the etiology of HCM. In 87 Danish HCM patients, full mtDNA sequencing revealed 446 variants. After elimination of 312 (69.9%) non-coding and synonymous variants, a further 109 (24.4%) with a global prevalence > 0.1%, three (0.7%) haplogroup associated and 19 (2.0%) variants with a low predicted in silico likelihood of pathogenicity, three variants: MT-TC: m.5772G>A, MT-TF: m.644A>G, and MT-CYB: m.15024G>A, p.C93Y remained. A detailed analysis of these variants indicated that none of them are likely to cause HCM. In conclusion, private mtDNA mutations are frequent, but they are rarely, if ever, associated with HCM.

Targeted exome analysis of Russian patients with hypertrophic cardiomyopathy

“…Hypertrophic cardiomyopathy is predominantly a genetically caused disorder with an autosomal dominant type of inheritance (Greaves et al, 1987 ; Ho et al, 2015 ; Maron & Maron, 2013 ; Maron et al, 2012 ). Rare autosomal recessive and X‐linked types of inheritance have also been described (Branzi et al, 1985 ; Hagen et al, 2015 ; Hartmannova et al, 2013 ; Santorelli et al, 1999 ) and may be a phenocopy condition (Marian, 2016 ). Moreover, numerous sporadic cases associated with de novo pathogenic variants have also been reported (Maron et al, 2012 ; Watkins et al, 1995 ).…”

Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy

“…Hypertrophic cardiomyopathy (HCM), classically defined as the presence of idiopathic left ventricular hypertrophy, is the most common heritable cardiovascular disease (affecting at least 1 in 500 individuals); it is typically transmitted in an autosomal dominant pattern ( 1 – 3 ); however, sporadic cases associated with de novo mutations ( 1 , 4 ) and patients with maternally-inherited HCM ( 5 , 6 ) have also been reported. HCM is recognized as an important cause of sudden cardiac death (SCD), heart failure and embolic stroke secondary to atrial fibrillation ( 2 ).…”

MITOCHONDRIAL DNA POLYMORPHISM AND PATHOGENETICS OF SUDDEN CARDIAC DEATH (review)

“…Известно также, что гаплогруппа Т мтДНК в испанской популяции у больных с гипертрофической кардиомиопатией встречается с более высокой частотой, чем в популяционной выборке [24]. В популяции датчан у пациентов с гипертрофической кардиомиопатией чаще регистрируется (по сравнению с популяцией) гаплогруппа Н [30]. Приведенные данные свидетельствуют о том, что полиморфизм мтДНК вносит определенный вклад в предрасположенность к развитию критических состояний в сердечно-сосудистом континууме.…”