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Revista Española de Cardiología (English Edition) Revista Española de Cardiología (English Edition)
Rev Esp Cardiol. 2018;71:545-52 - Vol. 71 Num.07 DOI: 10.1016/j.rec.2017.10.013

In-frame Variants in FLNA Proximal Rod 1 Domain Associate With a Predominant Cardiac Valvular Phenotype

Luis Fernández a,b,, Jair Tenorio a,b, Coral Polo-Vaquero a,b, Elena Vallespín a,b, María Palomares-Bralo a,b, Sixto García-Miñaúr a,b, Fernando Santos-Simarro a,b, Pedro Arias a,b, Hernán Carnicer c, Silvina Giannivelli c, Juan Medina d, Rosa Pérez-Piaya c, Jorge Solís d, Mónica Rodríguez e, Alexandra Villagrá e, Laura Rodríguez f, Julián Nevado a,b, Víctor Martínez-Glez a,b, Karen E. Heath a,b, Pablo Lapunzina a,b,g

a Instituto de Genética Médica y Molecular (INGEMM), Instituto de Investigación del Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
b Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
c Unidad de Pediatría, Hospital Universitario HM Montepríncipe, Madrid, Spain
d Unidad de Cardiología, Hospital Universitario HM Montepríncipe, Madrid, Spain
e Unidad de Cardiología Infantil, Hospital Universitario HM Montepríncipe, Madrid, Spain
f Laboratorio Clínico, Hospital Universitario HM Montepríncipe, Madrid, Spain
g Unidad de Genética Clínica, Hospital Universitario HM Montepríncipe, Madrid, Spain

Keywords

X-linked disease. Cardiac valvular dysplasia. FLNA mutation.

Abstract

Introduction and objectives

X-linked cardiac valvular dysplasia is a rare form of male-specific congenital heart defect mainly characterized by myxomatous degeneration of the atrioventricular valves with variable hemodynamic consequences. It is caused by genetic defects in FLNA-encoded filamin A, a widely expressed actin-binding protein that regulates cytoskeleton organization. Filamin A loss of function has also been associated with often concurring neurologic and connective tissue manifestations, with mutations in the first half of the Rod 1 domain apparently expressing the full cardiac phenotype. We contribute to previous genotype-phenotype correlations with a multidisciplinary approach in a newly-described family.

Methods

Cardiologic, dysmorphologic, and genetic evaluation of available members were complemented with transcriptional and X-chromosome inactivation studies.

Results

A novel FLNA mutation c.1066-3C>G cosegregated with a male-expressed, apparently isolated, cardiac phenotype with no skewed X-inactivation pattern in female carriers. This variant was shown to result in an in-frame deletion of 8 amino acid residues near the N-terminal region of the protein.

Conclusions

A nonimprinted, partial loss of function of filamin A proximal Rod 1 domain seems to be the pathogenetic mechanism of cardiac valvular dysplasia, with some cases occasionally expressing associated extracardiac manifestations.

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1885-5857/© 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved

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