Adenine nucleotide translocase 1 associated hypertrophic cardiomyopathy: Association of mitochondrial haplogroup and phenotypic differences in a Mennonite family

Hypertrophic cardiomyopathy (HCM) is characterized by a thickening of the left ventricular wall. It has many causes one of which is genetics. A Mennonite family was found with a recessive ANT1 mutation causing HCM. The more common autosomal dominant ANT1 mutations most often cause progressive external ophthalmoplegia. Preliminary studies of the family revealed a difference in severity of HCM among affected individuals. The purpose of this study was to determine if mitochondrial haplogroup is associated with the difference in HCM severity. Thirteen cardiac parameters from homozygous mutant, heterozygous, and wild-type family members were collected by echocardiography and velocity vector imaging and analyzed based on mtDNA haplogroup. Mitochondrial haplogroup was determined for each of five maternal lineages in the family. The two major haplogroups, H and U, were identified. Detailed statistical analysis revealed four of the thirteen (4/13) cardiac parameters to be statistically significant in homozygous individuals when compared by haplogroup. Haplogroup U homozygous individuals had elevated IVS, LVPW, and LV mass values and lower apical rotation rates when compared to haplogroup H. These differences demonstrate that haplogroup U individuals have a more severe HCM phenotype than haplogroup H and thus mtDNA haplogroup U is associated with a more severe ANT1 associated HCM phenotype.