A Novel In-Frame Deletion of FLNA in X-Linked Cardiac Valvular Dysplasia With Variable Clinical Spectrum
Noboru Uchida1,2,3, Osamu Ohara4, Seigo Yukisawa2,5
1Department of Pediatrics, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan.
Insights
Researchers identified a new FLNA gene variant, p.Val675_Lys676del, causing X-linked cardiac valvular dysplasia (XCVD). This smallest in-frame deletion expands understanding of XCVD genetics and variable patient phenotypes, including extracardiac features.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- X-linked cardiac valvular dysplasia (XCVD) is linked to FLNA gene variants.
- Previous studies identified missense or in-frame deletion variants in FLNA associated with XCVD.
Purpose of the Study:
- To identify the genetic cause of cardiac valvular dysplasia in a Japanese family.
- To characterize a novel FLNA variant and its impact on XCVD.
Main Methods:
- Genetic analysis of affected family members.
- Splicing analysis and in silico structural modeling of the FLNA variant.
- Phenotypic evaluation including clinical examination and brain MRI.
Main Results:
- A novel hemizygous FLNA variant, c.2023-6_2026delinsACGCT (p.Val675_Lys676del), was identified in three affected brothers.
- This variant represents the smallest in-frame deletion reported in XCVD.
- Patients exhibited variable disease severity and some presented with extracardiac features like skin hyperextensibility and joint hypermobility.
- Structural modeling indicated the deletion disrupts an alpha-helix, potentially impairing FLNA stability.
Conclusions:
- A novel, likely pathogenic FLNA variant (p.Val675_Lys676del) is identified as the cause of XCVD in this family.
- This finding expands the known spectrum of FLNA variants and associated phenotypes in XCVD.
- The study highlights the variable clinical presentation of XCVD, including extracardiac manifestations.
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.
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