Four-Generation Family With Ebstein Anomaly Highlights Future Challenges in Congenital Heart Disease Genetics.

Mercer et al1 describe a family in which a missense variant in Filamin A ( FLNA ) segregates with Ebstein anomaly. This is a syndromal form of congenital heart disease (CHD) in that affected individuals have craniofacial and musculoskeletal anomalies, as well as keloid scarring and oligodontia. Clinically, affected family members had no apparent neurological involvement, although cranial imaging was not reported. Overall, the phenotype is clearly in a continuum with other FLNA -associated disorders including otopalatodigital syndrome (OPD1 and OPD2) and Melnick–Needles syndrome. However, this represents a new addition to the stable phenotypes linked to FLNA , with the cardiac features being particularly noteworthy. See Article by Mercer et al Such families are a unique resource in expanding our knowledge of causal genes and mechanisms in CHD. The unfolding of this story (some of the family had previously been screened for NKX2-5 and MYH7 mutations in a previous era) over some 25 years, and 4 generations are testament to the persistence of the authors, as well as the effectiveness of modern sequencing technology. It also illustrates the power of the phenotype to illuminate the genotype. Previously, FLNA had been associated with cardiac valvular disease (not including Ebstein anomaly) …