Myocardial bridge (MB) is a congenital coronary artery anomaly and an important cause of chest pain. The genetic basis of this cardiac vasculopathy is unknown.

Whole-exomes sequencing technique was exploited to collect genetic information from MB and normal subjects. Genotypic differences were analyzed with GATK pipelines. Functional annotations were investigated via Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and knockout mouse database. Pathogenicity prediction was performed by ClinVar, CADD, and REVEL scoring systems.

From April 2020 to May 2021, 248 subjects who had undergone coronary angiographies were screened, and MBs were detected in 46 (18.5%) patients. MB severity was ranked based on the luminal area loss during systole. Eight pairs of angiographically-identified severe myocardial bridge patients and normal controls were enrolled for genetic analysis. One hundred and fifty-three candidate variants in 140 genes potentially pathogenic for MB were identified. Functional annotation of candidate genes indicated a significant association with abnormal skeletal muscle mass, cardiomyopathy, and transmembrane cation proteins. Genes with the most variants ranked from the ClinVar and CADD/REVEL were the TTN, DMD, and TCF7L1, SOX8, respectively. Combining the number of variants, existence in MB patients, and tissue expressions, TTN and DMD gene polymorphisms were the most significantly associated with the existence of a myocardial bridge. The TCF7L1 and SOX8 genes contributed to multiple loci of pathogenic variants, which collectively predicted 25% of MB. Gene variants on the 4 genes (TTN, DMD, TCF7L1, and SOX8) predicted MB with a sensitivity of 87.5% and a specificity of 100%. 

Genetic variants on TTN, DMD, TCF7L1, and SOX8 were highly associated with the myocardial bridge, especially the first two genes. Further studies would be needed to clarify the interplays between cardiac sarcomeric protein titin and cardiomyocyte anchoring protein dystrophin in the formation of the myocardial bridge.