Cardiovascular and connective tissue disorder features in FLNA-related PVNH patients: progress towards a refined delineation of this syndrome

Abstract

Background FLNA 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. Methods We 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. Results Half 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. Conclusion In 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.

Phenotypic manifestations inFLNA-related periventricular nodular heterotopia: a case report and review of the literature

“…In a review of 92 patients, frameshift and missense variants were identified as the most common variant types (n=34 and n=20, respectively) 24. Interestingly, the actin-binding domain of FLNA was shown to be significantly enriched in pathogenic missense variants,24 which is where we also detected the novel missense variant in our patient.…”

“…In a review of 92 patients, frameshift and missense variants were identified as the most common variant types (n=34 and n=20, respectively) 24. Interestingly, the actin-binding domain of FLNA was shown to be significantly enriched in pathogenic missense variants,24 which is where we also detected the novel missense variant in our patient. Although no functional studies were conducted, the novel missense variant in our patient was re-classified as likely pathogenic based on the convincing clinical findings (PVNH), the de novo occurrence, the rarity of the variant in control populations (gnomAD) and in silico predicted pathogenicity.…”

“…They described various skin findings in all the patients including easy bruising, soft, thin, translucent or hyperelastic skin, indicating heterogeneity in the cutaneous manifestations 12. Other PVNH patients have also been reported with an EDS-like phenotype characterised by joint hypermobility, recurrent dislocations, skin anomalies and aorta aneurysms 11 18 21–24. The EDS-PVNH phenotype is proposed to be regarded as a part of the clinical FLNA-PVNH spectrum, and not as a separate subtype 12…”

Periventricular Heterotopia and Novel FLNA Gene Variant: Clinical and Neuroimaging Clues for an Early Diagnosis

“…Connective tissue disorder features in FLNA -related PNH patients have already been reported. 3, 6, 7…”

“…3 FLNA loss-of-function variants can cause isolated or combined PNH, cardiovascular malformations, and connective tissue disorders or gut dysmotility. [4][5][6][7] In addition, it has recently been associated with early-life onset of progressive respiratory disease and hypoxemia due to its role in alveolar growth. 8 Brain magnetic resonance imaging (MRI) is considered the gold standard for diagnosis.…”