Phenotypic and genotypic insights, counseling strategies, and follow-up in 24 individuals with filamin a deficiency: findings from a retrospective cohort study

Background: Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration. Loss-of-function (LOF) variants give rise to a wide variety of symptoms with periventricular nodular heterotopia (PVNH) and epilepsy as the most common features. FLNA deficiency manifests as a multisystemic disorder with abnormalities of connective tissue and involvement of the cardiovascular, pulmonary, gastrointestinal and hematological system. Affected individuals need a multidisciplinary follow-up, but guidelines are lacking. Here, we present findings from a monocentric cross-sectional cohort study as a basis for improving clinical practices and surveillance for individuals with FLNA deficiency.

Results: 24 index patients with FLNA deficiency were identified. In the cohort, 23 patients exhibited clinical features of PVNH, while one individual presented with congenital pulmonary airway malformation (CPAM). The incidence of clinical features such as epilepsy (84%) and cardiovascular involvement (56%) align with previously published cohorts. Systematic multidisciplinary follow-up, particularly regular cardiological screening, was lacking in a significant number of individuals. Additionally, lesser-known symptoms such as constipation and thrombocytopenia were underreported, highlighting the need for comprehensive phenotypic assessment in FLNA deficiency.

Conclusion: The incidence of clinical features in this tertiary cohort aligns with existing literature. The absence of uniform and multidisciplinary guidelines hampers effective surveillance and management. Implementation of regular cardiological screening and increased awareness of less overt symptoms could improve medical outcomes for individuals with pathogenic FLNA variants.

Keywords: Filamin a (FLNA); Genetic counseling; Malformation of Cortical Development; Neuronal migration disorder; Periventricular nodular heterotopia.