FHOD3

Inheritance Pattern: AD

Disease ID:MONDO:0030317

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030317

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: Illumina

The FHOD3 gene is located on chromosome 18 at 18q12.2 and encodes the formin homology 2 domain containing 3, which is associated with actin organization. The FHOD3 gene was first reported in relation to autosomal dominant hypertrophic cardiomyopathy in 2018 (30442288: Ochoa et al. 2018). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least five unrelated probands in two publications (30442288: Ochoa et al. 2018; 31742804: Huang et al. 2019). Variants in this gene segregated with disease in one large seven-generation family and in multiple nuclear families (30442288: Ochoa et al. 2018). The mechanism of disease has not been clearly defined, but both missense and in-frame deletion variants have been associated with disease (30442288: Ochoa et al. 2018; 31742804: Huang et al. 2019). This gene-disease relationship is supported by expression data in the developing heart and sarcomeres and functional alteration in non-patient cells demonstrating impaired myofibril maintenance and defective polymerization of actin filaments in cardiomyocytes (21149568: Iskratsch et al. 2010; 26848968: Fujimoto et al. 2016). Rescue experiments in cultured cardiomyocytes and a transgenic mouse line also support a role for FHOD3 in the developing sarcomere (19706596: Taniguchi et al. 2009; 26848968: Fujimoto et al. 2016). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

FHOD3 was first reported in relation to autosomal dominant hypertrophic cardiomyopathy in 2018 (Ochoa et al., PMID: 30442288). Over 50 variants (missense, nonsense, splice variants and in frame del/dup variants) that have been reported in over 100 probands in 6 publications (PMIDs: 29907873, 30442288, 30898215, 31742804, 32335906, 33586461) are included in this curation. The majority of variants are located at exon 12 and exon 15, including two recurring variants p.Ser527del and p.Tyr528Cys in exon 12. Most reported variants are missense with a smaller number of truncating, CNV and splice variants identified at these locations. Two CNVs were too large to be registered, an 11kb deletion from c.1836-1527 in intron 14 to c.2022-2042 in intron 16 and an 11kb deletion c.1836-2543 in intron 14 to c.2021+2217 in intron 16, but contribute 0.25 points each to the overall score (Ochoa JP, et al., 2020, PMID: 32335906). The mechanism of pathogenicity is unknown. This gene-disease relationship is also supported by expression studies, protein interaction, functional alteration and animal models (PMIDs: 15966898, 19706596, 29158260, 29686099, 23213483). However, it should be noted that while experimental studies have shown an important role for FHOD3 in heart and sarcomeric development, no studies have demonstrated a clear HCM phenotype. In summary, there is definitive evidence supporting the relationship between FHOD3 and autosomal dominant hypertrophic cardiomyopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Hereditary Cardiovascular Diseases GCEP on the meeting date September 29, 2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0030317

Submitter: Ambry Genetics