Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.

Background: Myxomatous dystrophy of the cardiac valves affects approximately 3% of the population and remains one of the most common indications for valvular surgery. Familial inheritance has been demonstrated with autosomal and X-linked transmission, but no specific molecular abnormalities have been documented in isolated nonsyndromic forms. We have investigated the genetic causes of X-linked myxomatous valvular dystrophy (XMVD) previously mapped to chromosome Xq28.

Methods And Results: A familial and genealogical survey led us to expand the size of a large, previously identified family affected by XMVD and to refine the XMVD locus to a 2.5-Mb region. A standard positional cloning approach identified a P637Q mutation in the filamin A (FLNA) gene in all affected members. Two other missense mutations (G288R and V711D) and a 1944-bp genomic deletion coding for exons 16 to 19 in the FLNA gene were identified in 3 additional, smaller, unrelated families affected by valvular dystrophy, which demonstrates the responsibility of FLNA as a cause of XMVD. Among carriers of FLNA mutation, the penetrance of the disease was complete in men and incomplete in women. Female carriers could be mildly affected, and the severity of the disease was highly variable among mutation carriers.

Conclusions: Our data demonstrate that FLNA is the first gene known to cause isolated nonsyndromic MVD. This is the first step to understanding the pathophysiological mechanisms of the disease and to defining pathways that may lead to valvular dystrophy. Screening for FLNA mutations could be important for families affected by XMVD to provide adequate follow-up and genetic counseling.