Genome-Wide Association and Inheritance-Based Analyses Implicate Unconventional Myosin Genes in Hypoplastic Left...

Area of Science:

• Genetics
• Cardiovascular Biology
• Developmental Biology

Background:

• Hypoplastic left heart syndrome (HLHS) pathogenesis is complex due to genetic diversity and multiple gene involvement.
• Understanding HLHS requires deciphering its intricate genetic underpinnings.

Purpose of the Study:

• To identify candidate genes associated with HLHS using whole genome sequencing.
• To analyze genetic variants contributing to HLHS susceptibility through multiple analytical strategies.

Main Methods:

• Whole genome sequencing of HLHS cases and controls.
• Genome-wide association study (GWAS) and transmission disequilibrium testing (TDT).
• Filtering of rare, predicted-damaging variants in multiplex HLHS families.

Main Results:

• GWAS identified a suggestive association with a MYO18B intron variant (rs2269628-G).
• TDT revealed significant overrepresentation of a MYO18B intron variant (rs73154186-A) in HLHS trios.
• Rare variants in MYO5A and MYO15A were identified in multiplex families, suggesting oligogenic inheritance patterns.

Conclusions:

• Common and rare alleles in unconventional myosin genes are associated with HLHS.
• MYO18B's role in cardiac sarcomerogenesis supports a myogenic perturbation hypothesis in HLHS development.