Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing

Area of Science:

• Cardiovascular Genetics
• Genomic Medicine
• Molecular Cardiology

Background:

• Interpreting rare variants from high-throughput sequencing (HTS) in hypertrophic cardiomyopathy (HCM) presents a clinical challenge.
• A targeted HTS approach was developed for inherited cardiovascular diseases, including HCM.
• Quantifying the evidence for variant causality is crucial for clinical application.

Purpose of the Study:

• To explore the clinical implications of HTS in HCM patients.
• To analyze coding, intronic, and regulatory regions of 41 cardiovascular genes.
• To compare sequencing results with published data and large-scale exome screens.

Main Methods:

• Studied 223 unrelated HCM patients using targeted HTS.
• Employed solution-based sequence capture and massive parallel resequencing.
• Defined rare variants (frequency <0.5%) in non-synonymous, loss-of-function, and splice-site regions as candidates.

Main Results:

• Identified 152 distinct candidate variants (89 novel) in sarcomeric genes in 143 patients (64%), excluding titin.
• Found excess rare single non-synonymous single-nucleotide polymorphisms (nsSNPs) in MYH7, MYBPC3, TNNI3, and TNNT2.
• Detected 94 additional candidate variants (73 novel) in desmosomal and ion-channel genes in 96 patients (43%).

Conclusions:

• This is the first large-scale quantitative analysis of sarcomere protein gene variants in HCM using HTS.
• The study highlights a significant number of rare variants of unknown clinical significance in genes associated with inherited cardiac disease.
• HTS provides valuable insights into the genetic landscape of HCM.