MYH7 – Ebstein Anomaly

Ebstein anomaly is a rare congenital malformation of the tricuspid valve characterized by apical displacement of the septal leaflet. Familial cases account for a minority, implicating genetic etiologies. Emerging evidence implicates heterozygous variants in MYH7, encoding the β-myosin heavy chain, in a subset of patients with Ebstein anomaly often accompanied by ventricular septal defects (HP:0001629) and left ventricular noncompaction (HP:0030682).

In a population-based cohort of 141 unrelated probands with Ebstein anomaly, mutational screening of MYH7 identified heterozygous mutations in 8 (6%) individuals (PMID:21127202). Seven were missense and one a 3-bp deletion. Six of the 8 mutation-positive probands exhibited coexistent LVNC, highlighting a specific subset. Co-segregation of LVNC with the MYH7 variant was observed in 3 pedigrees, including one with an additional relative with Ebstein anomaly, underscoring a dominant transmission pattern.

A multigenerational family reported a c.3658_3660del (p.Glu1220del) variant in MYH7 segregating with Ebstein anomaly in 4 genetically tested individuals across two generations (PMID:23956225). Affected members displayed variable cardiac phenotypes including ventricular septal defects and left ventricular hypertrabeculation. The variant arose de novo in the father and transmits in an autosomal dominant manner, confirming pathogenicity.

A splicing variant NM_000257.4:c.732+1G>A has been identified in a fetus with Ebstein anomaly and in three maternal relatives with disparate phenotypes ranging from isolated LVNC to asymptomatic carrier status (PMID:35209905). Absence of PCR products in mutant carriers suggests complete loss of normal transcript. This allele demonstrates variable expressivity under an autosomal dominant inheritance model.

Functional studies of MYH7 variants in heterologous systems and mouse models, although primarily in hypertrophic or dilated cardiomyopathy contexts, establish that missense mutations such as p.Arg403Gln and p.Tyr283Asp disrupt actin-activated ATPase activity and in vitro motility (PMID:8294404, PMID:9172070). These data support a mechanism of sarcomere-mediated developmental perturbation during cardiogenesis.

Collectively, 14 probands including 8 unrelated individuals, two families with clear autosomal dominant segregation of Ebstein anomaly, and supportive functional evidence fulfill criteria for a Strong clinical validity rating. No studies to date report conflicting evidence against this association.

Genetic testing for MYH7 should be considered in patients with Ebstein anomaly, particularly when accompanied by ventricular septal defects or left ventricular noncompaction, to inform family screening and management strategies.

References

• Circulation. Cardiovascular genetics | 2011 | Mutations in the sarcomere gene MYH7 in Ebstein anomaly. PMID:21127202
• American journal of medical genetics. Part A | 2013 | Familial ebstein anomaly, left ventricular hypertrabeculation, and ventricular septal defect associated with a MYH7 mutation. PMID:23956225
• BMC medical genomics | 2022 | Diverse cardiac phenotypes among different carriers of the same MYH7 splicing variant allele (c.732+1G>A) from a family. PMID:35209905
• The Journal of biological chemistry | 1994 | Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. PMID:8294404
• Journal of muscle research and cell motility | 1997 | The in vitro motility activity of beta-cardiac myosin depends on the nature of the beta-myosin heavy chain gene mutation in hypertrophic cardiomyopathy. PMID:9172070

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