Key result
FHOD3 copy-number deletions occur in ~0.05% of HCM probands but remain absent in controls.
Why the study?
Although FHOD3 has emerged as a novel disease-causing gene for HCM, the relevance and clinical implication of copy-number variations (CNVs) have not been determined.
Does next-generation sequencing for copy-number variations in FHOD3 identify disease-causing mutations in patients with hypertrophic cardiomyopathy?
Case-Control (n=8,466)
Does next-generation sequencing for copy-number variations in FHOD3 identify disease-causing mutations in patients with hypertrophic cardiomyopathy?
Absolute Event Rate: 0.05% vs 0%
Systematic CNV analysis in NGS panels for HCM can identify pathogenic FHOD3 deletions, reinforcing the gene's relevance and potentially increasing diagnostic yield.
Rare FHOD3 exon 15-16 deletions may explain select HCM cases; leaves open routine CNV inclusion in panels.
Despite new strategies, such as evaluating deep intronic variants and new genes in whole-genome-sequencing studies, the diagnostic yield of genetic testing in hypertrophic cardiomyopathy (HCM) is still around 50%. FHOD3 has emerged as a novel disease-causing gene for this phenotype, but the relevance and clinical implication of copy-number variations (CNVs) have not been determined. In this study, CNVs were evaluated using a comparative depth-of-coverage strategy by next-generation sequencing (NGS) in 5493 HCM probands and 2973 disease-controls. We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group). These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM. The clinical characteristics of the affected carriers were consistent with those reported in FHOD3 in previous studies. This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease.
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Ochoa et al. (2020) conducted a case-control in Hypertrophic cardiomyopathy (n=8,466). Copy-number variations (CNVs) in FHOD3 vs. Disease-controls was evaluated on Detection of symmetrical deletions in FHOD3. Copy-number variations in FHOD3, specifically deletions involving exons 15 and 16, were detected in 3 of 5,493 hypertrophic cardiomyopathy probands and 0 of 2,973 disease-controls.
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