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