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

Clarisse Billon, Salma Adham, Natalia Hernandez Poblete, Anne Legrand, Michael Frank, Laurent Chiche, Stephane Zuily, Karelle Benistan, Laurent Savale, Khaoula Zaafrane-Khachnaoui, Anne-Claire Brehin, Laurence Bal, Tiffany Busa, Mélanie Fradin, Chloé Quelin, Bertrand Chesneau, Denis Wahl, Patricia Fergelot, Cyril Goizet, Tristan Mirault, Xavier Jeunemaitre, Juliette Albuisson, Anne Dieux, Fabien Labombarda, Sylvain Rheims, Odile Boute, André Vincentelli, Annick Toutain, Sylvie Odent, Gaetan Lesca, Marie Vincent, Juliette Piard, Maud Favier, Philippe Derambure, Patrick Edery, Susanne Thummler, Marion Gérard, Fanny Morice-Picard, Valérie Layet, Cécile Laroche, Laurent Pasquier, Elisabeth Sarrazin, Thierry Billette de Villemeur, Lucie Guyant-Marechal,
Orphanet J Rare Dis. 2021-12-01; 16(1):
DOI: 10.1186/s13023-021-02128-1

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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.

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.

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.

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.

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