A Novel In-Frame Deletion of FLNA in X-Linked Cardiac Valvular Dysplasia With Variable Clinical Spectrum

ABSTRACT

X-linked cardiac valvular dysplasia (XCVD) has been associated with missense or in-frame deletion variants in FLNA. We report a Japanese family with cardiac valvular dysplasia. The proband was diagnosed with multiple valve dysplasia at a primary school health checkup. He also exhibited skin hyperextensibility and joint hypermobility. His younger monozygotic twin brothers were diagnosed with multiple valve dysplasia during their 1-month pediatric checkups. One of them exhibited severe valvular disease and required aortic and mitral valve replacement at age 16 due to progressive regurgitation. All three patients showed no developmental delay or evidence of periventricular nodular heterotopia on brain MRI. We identified a novel hemizygous FLNA variant, NM_001456.4(FLNA):c.2023-6_2026delinsACGCT, in all three patients. Splicing analysis revealed an in-frame deletion of two amino acids, p.Val675_Lys676del. No significant difference was observed in overall expression levels of FLNA transcript between the patient and a healthy individual. In silico structural modeling revealed that this deletion disrupts an α-helix positioned between β-strands of domains 4 and 5, which would impair the structural stability of FLNA. This variant was not found in public genomic databases. In conclusion, we identified a novel likely pathogenic variant in FLNA, p.Val675_Lys676del, the smallest in-frame deletion reported to date in XCVD. Patients with this variant showed variable severity, and some presented with extracardiac features. Our findings expand both the genetic and phenotypic spectrum of XCVD.