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Background <p>FLNA encodes filamin A, a cytoskeletal actin-binding protein with critical roles in neuronal migration, mechano-transduction, and organ morphogenesis. Pathogenic FLNA variants are classically associated with periventricular nodular heterotopia (PVNH), epilepsy, and multisystem manifestations, although interpretation of missense variants remains challenging because of marked variable expressivity and limited functional evidence.</p> Methods <p>We describe a mother–daughter pair carrying the heterozygous FLNA missense variant c.5776&#xa0;C &gt; T (p.Pro1926Ser). Clinical, electroencephalographic, neuroradiological, cardiological, and genetic data were retrospectively reviewed. Variant interpretation was performed according to ACMG/AMP criteria and supported by in silico and structural analyses.</p> Results <p>The proband, a 13-year-old girl, presented with migraine with aura, epilepsy responsive to levetiracetam, normal brain MRI, and QT interval prolongation, with no pathogenic variants identified in established long-QT genes. Her mother, who carried the same variant, had focal epilepsy, migraine with aura, and subtle PVNH on brain MRI. Additional family history included a maternally related male cousin reportedly hemizygous for the same variant and affected by a severe congenital multisystem phenotype including valvular and extracerebral abnormalities, overall consistent with FLNA-related disease. The p.Pro1926Ser substitution was absent from population databases, involved a highly conserved residue within immunoglobulin-like repeat 17 of the rod-2 domain, and was predicted to be deleterious by most computational tools.</p> Conclusions <p>These findings support a likely contributory role of FLNA p.Pro1926Ser in a variably expressive neurodevelopmental and multisystem disorder in which epilepsy represents the predominant neurological phenotype.</p>

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A novel FLNA missense variant in a mother–daughter pair with epilepsy: case series evidence of variable multisystem expressivity

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Alessandro Bombaci,
  • Emanuele Micaglio,
  • Sara Benedetti,
  • Gianluca Stufano,
  • Gianni Cutillo,
  • Gabriella Doddato,
  • Sergio Soeren Rossi,
  • Salvatore Mazzeo,
  • Carlo Pappone,
  • Massimo Filippi,
  • Maria Salsone

摘要

Background

FLNA encodes filamin A, a cytoskeletal actin-binding protein with critical roles in neuronal migration, mechano-transduction, and organ morphogenesis. Pathogenic FLNA variants are classically associated with periventricular nodular heterotopia (PVNH), epilepsy, and multisystem manifestations, although interpretation of missense variants remains challenging because of marked variable expressivity and limited functional evidence.

Methods

We describe a mother–daughter pair carrying the heterozygous FLNA missense variant c.5776 C > T (p.Pro1926Ser). Clinical, electroencephalographic, neuroradiological, cardiological, and genetic data were retrospectively reviewed. Variant interpretation was performed according to ACMG/AMP criteria and supported by in silico and structural analyses.

Results

The proband, a 13-year-old girl, presented with migraine with aura, epilepsy responsive to levetiracetam, normal brain MRI, and QT interval prolongation, with no pathogenic variants identified in established long-QT genes. Her mother, who carried the same variant, had focal epilepsy, migraine with aura, and subtle PVNH on brain MRI. Additional family history included a maternally related male cousin reportedly hemizygous for the same variant and affected by a severe congenital multisystem phenotype including valvular and extracerebral abnormalities, overall consistent with FLNA-related disease. The p.Pro1926Ser substitution was absent from population databases, involved a highly conserved residue within immunoglobulin-like repeat 17 of the rod-2 domain, and was predicted to be deleterious by most computational tools.

Conclusions

These findings support a likely contributory role of FLNA p.Pro1926Ser in a variably expressive neurodevelopmental and multisystem disorder in which epilepsy represents the predominant neurological phenotype.