Author + information
- Christopher Semsarian, MBBS, PhD, MPH,
- Jodie Ingles, MPH, PhD and
- Richard D. Bagnall, PhD∗ ()
- ↵∗Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia
Ochoa et al. (1) recently demonstrated a significantly higher frequency of rare protein-altering variants in the formin homology domain containing 3 gene (FHOD3) in hypertrophic cardiomyopathy (HCM) probands than in disease control subjects. The 2 most commonly identified variants, found in 18 probands, affect consecutive amino acids, Ser527del and Tyr528Cys, and cosegregate with HCM in multiple families.
In a recent issue of the Journal, we reported our experience with using genome sequencing to improve outcomes of genetic testing in patients with HCM (2). One benefit of having genome sequencing data available is to quickly assess new genes as they are reported, and here, we demonstrate this for FHOD3. We found a 9-nucleotide insertion (c.1571_1579dup), adding 3 amino acids after Phe526 in a proband and affected member of 1 family (Figure 1). We also found 2 different variants affecting the same essential splice donor nucleotide of exon 12: c.1646+1G>C segregated in 3 affected members of 1 family, and c.1646+1G>A was found in 2 unrelated probands (Figure 1). Both splice site variants predict skipping of exon 12, leading to an in-frame deletion of 120 amino acids after Ser429. Exon 12 is specific to the main FHOD3 isoform found in the adult ventricular myocardium and is required for targeting the FHOD3 protein to the myofibrils in cardiomyocytes.
The FHOD3 variants in our cohort lead to an in-frame insertion or deletion in a nonrepetitive region, are reported in ≤1 individual of the gnomAD database of population controls, and cosegregate with disease, or are found in at least 2 unrelated individuals with the same phenotype; hence, they are likely pathogenic according to the classification criteria of Ochoa et al. (1). Revisiting our genome sequencing data for FHOD3 variants has thus increased the diagnostic yield from 20% to 28%. Collectively, we demonstrate how genome sequencing data provides an archive of variants to be reassessed as new disease genes are reported.
Please note: Dr. Semsarian is the recipient of a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (#1059156). Dr. Ingles is a recipient of a Heart Foundation of Australia Future Leader Fellowship (#100833). Dr. Bagnall reported that he has no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation
- Ochoa J.P.,
- Sabater-Molina M.,
- Garcia-Pinilla J.M.,
- et al.
- Bagnall R.D.,
- Ingles J.,
- Dinger M.E.,
- et al.