Variantes que mantienen el marco de lectura en el dominio Rod 1 proximal del gen FLNA se asocian con un predominio del fenotipo valvula / In-frame variants in FLNA proximal Rod 1 domain associate with a predominant cardiac valvular phenotype

Introducción y objetivos: La displasia valvular cardiaca ligada al cromosoma X es una cardiopatía congénita rara específica del sexo masculino y caracterizada principalmente por una degeneración mixomatosa de las válvulas auriculoventriculares con consecuencias hemodinámicas variables. Se debe a defectos genéticos en la filamina A (codificada por FLNA), una proteína de unión a actina de expresión ubicua que regula la organización del citoesqueleto. La pérdida de función de la filamina A también se ha asociado con manifestaciones neurológicas y del tejido conectivo a menudo simultáneas, y aparentemente las mutaciones en la primera mitad del dominio Rod 1 expresan el fenotipo cardiaco completo. En esta familia de nueva descripción, se ha contribuido a las correlaciones genotipo-fenotipo previas con un enfoque multidisciplinario. Métodos: La evaluación cardiológica, dismorfológica y genética de los miembros disponibles se complementó con estudios de la transcripción y de la inactivación del cromosoma X. Resultados: La nueva mutación de FLNA c.1066-3C>G cosegregaba con un fenotipo cardiaco aparentemente aislado y expresado en los varones, sin que hubiera un sesgo en el patrón de inactivación del cromosoma X en las mujeres portadoras. Esta variante resultó en una deleción dentro del marco de lectura de 8 residuos de aminoácidos cercanos a la región N-terminal de la proteína. Conclusiones: La pérdida de función parcial y no sometida a impronta del dominio Rod 1 proximal de la filamina A parece ser el mecanismo patogénico de la displasia valvular cardiaca, expresada en algunos casos con manifestaciones extracardiacas

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

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

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.