Fig. 4

The genotype–phenotype relationship for MYH6 in the “second variant” hypothesis. mutations in MYH6 is responsible for degenerative heart diseases or cardiac malformations of varying severity. Three main genotypes are thought to be responsible for these diseases: (i) classical autosomal-recessive inheritance of two rare, pathogenic MYH6 variants, responsible for the most severe phenotype; (ii) synergistic heterozygosity, i.e. the combination of a single pathogenic MYH6 variant with a modifier variant in an interacting gene (FLNC in this case), and (iii) variable compound heterozygosity, i.e. the combination of a single MYH6 pathogenic variant with one or more common MYH6 variants, with intrafamily variability. ASD: atrial septal defect, AV: aortic valve, Coarc: coarctation, FLNC: filamin C, HCM: hypertrophic cardiomyopathy, HLHS: hypoplastic left heart syndrome