Strengthening the Genetic Evidence for the FLNA c.5776C>T (p.Pro1926Ser) Variant: Comments on Segregation, X-inactivation, and Digenic Considerations

Background: We read with interest the reported mother–daughter case series describing the novel heterozygous FLNA c.5776C>T (p.Pro1926Ser) variant associated with epilepsy and variable multisystem manifestations. Discussion: We highlight several considerations that may further strengthen the evidence supporting the pathogenicity and clinical interpretation of this variant. These include the need for direct confirmation of the reported hemizygous male relative’s carrier status, broader segregation testing in unaffected maternal relatives, and functional assessment of tissue-specific skewed X-chromosome inactivation. We also discuss whether the ALG13 p.Met557Ile variant identified in the proband could have a phenotype-modifying or digenic contribution. Finally, the reported QTc prolongation and limitations of 1.5T MRI warrant continued cardiological follow-up and consideration of higher-resolution epilepsy-protocol MRI. Conclusion: Additional segregation, X-inactivation, and functional evidence may help clarify the pathogenicity and variable expressivity of the FLNA p.Pro1926Ser variant and contribute to its eventual reclassification.