Abstract
BackgroundFLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition.MethodsWe retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review.ResultsHalf of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein.ConclusionIn FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms.
Highlights
FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowl‐ edged cause of seizures of various types
First we described the characteristics of patients carrying FLNA LoF variants in whom genetic testing was performed because of CV or connective tissue disorders (CTD) features
Cohort 1 FLNA pathogenic variants were identified in 10 female Index-Cases of median age 38 years [range 14–66] (Table 1)
Summary
FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowl‐ edged cause of seizures of various types. Pathogenic variants in the X-linked FLNA gene encoding Filamin-A, a widely expressed cytoskeletal protein, lead to highly variable clinical presentations including periventricular nodular heterotopia type 1 (PVNH1, OMIM #300049). The disease is X-linked dominantly inherited and essentially affects women carrying heterozygous loss-of-function (LoF) pathogenic variants. To date, published LoF pathogenic variants are found all along the protein and their location is not predictive of the severity of the phenotype. One intervening calpain-sensitive “hinge” sequence is located between these two ROD domains (Hinge). C-terminal domain (Cter), where dimerization of filamin is mediated, is defined with the Ig-like repeat 24 and one “hinge” sequence located between Ig-like repeats 23 and 24 (Hinge 2) [8]
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