Mitral valve prolapse (MVP) by Barlow disease is recognized a genetic disease. Fibro-elastic deficiency (FED)-MVP is considered a pure degenerative condition. FLNA, the first gene involved in MVP, encodes for Filamin-A, a cytoskeleton associated protein. It interacts with a protein named Filgap, encoded by ARHGAP24 (Chr. 4), in the mechanical transduction. We hypothesized that ARHGAP24 mutations could elicit MVP with same pathway.

Four probands with ARHGAP24 mutations were identified among 96 MVP. By a familial echocardiographic screening we enrolled 19 adults of whom 13 had an ARHGAP24 mutation. The mutated group was matched with a control group of 39 healthy adults. Anterior (AML) and posterior (PML) mitral leaflets length and thickness were measured. The coaptation point position was the ratio of coaptation height on the systolic annulus diameter. MVP (displacement>2mm above the annulus line), minimal systolic displacement (MSD, displacement<2mm) and abnormal antero-posterior coaptation position (AAC, ratio<60%) were assessed.

The conjunction of MSD and AAC defines a MVP prodromal form (MVP-prod).

There was no difference between the two groups on baseline characteristics. Leaflets were thin in the mutated group (PML: 2.7±1 vs 2.2±0.5mm in control, P=0.21, AML: 2.5±0.9 vs 2.1±0.4mm, P=0.25), as reported in FEDMVP. Only the PML was elongated (8.2±1.6 vs 6.0±1.2mm/m ², P=0.0003) in the mutated group, leading to an anterior displacement of the coaptation point (51±11 vs 66±7%, P=0.0003). Abnormal mitral phenotype (70% of MVP, 23% of MVP prod) and mitral regurgitation (93 vs 38%, P=0.0007) were frequent in the mutated group. Two probands were operated for severe MR related to chordal rupture; histological examination confirmed the leaflets thinness.

ARHGAP24 is the first gene for autosomal dominant inherited MVP. Our limited series of patients exhibit typical features of FED-MVP. Our results could change the paradigm of a pure degenerative disease for FED-MVP.