In-frame Variants in FLNA Proximal Rod 1 Domain Associate With a Predominant Cardiac Valvular Phenotype
Rev Esp Cardiol (Engl Ed). 2018 Jul;71(7):545-552.
doi: 10.1016/j.rec.2017.10.013.
Epub 2017 Nov 14.
[Article in
English,
Spanish]
Authors
Luis Fernández
1
, Jair Tenorio
2
, Coral Polo-Vaquero
2
, Elena Vallespín
2
, María Palomares-Bralo
2
, Sixto García-Miñaúr
2
, Fernando Santos-Simarro
2
, Pedro Arias
2
, Hernán Carnicer
3
, Silvina Giannivelli
3
, Juan Medina
4
, Rosa Pérez-Piaya
3
, Jorge Solís
4
, Mónica Rodríguez
5
, Alexandra Villagrá
5
, Laura Rodríguez
6
, Julián Nevado
2
, Víctor Martínez-Glez
2
, Karen E Heath
2
, Pablo Lapunzina
7
Affiliations
- 1 Instituto de Genética Médica y Molecular (INGEMM), Instituto de Investigación del Hospital Universitario La Paz (IdiPAZ), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Electronic address: lfernandezg@salud.madrid.org.
- 2 Instituto de Genética Médica y Molecular (INGEMM), Instituto de Investigación del Hospital Universitario La Paz (IdiPAZ), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
- 3 Unidad de Pediatría, Hospital Universitario HM Montepríncipe, Madrid, Spain.
- 4 Unidad de Cardiología, Hospital Universitario HM Montepríncipe, Madrid, Spain.
- 5 Unidad de Cardiología Infantil, Hospital Universitario HM Montepríncipe, Madrid, Spain.
- 6 Laboratorio Clínico, Hospital Universitario HM Montepríncipe, Madrid, Spain.
- 7 Instituto de Genética Médica y Molecular (INGEMM), Instituto de Investigación del Hospital Universitario La Paz (IdiPAZ), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Unidad de Genética Clínica, Hospital Universitario HM Montepríncipe, Madrid, Spain.
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.
Keywords:
Cardiac valvular dysplasia; Displasia valvular cardiaca; Enfermedad ligada al cromosoma X; FLNA mutation; Mutación en FLNA; X-linked disease.
Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.
MeSH terms
-
Adult
-
Aged
-
Amino Acid Sequence / genetics*
-
Female
-
Filamins / genetics*
-
Genetic Diseases, X-Linked / genetics*
-
Genotype
-
Heart Defects, Congenital / genetics*
-
Heterozygote
-
Humans
-
Introns / genetics
-
Male
-
Mitral Valve Prolapse / genetics*
-
Myxoma / genetics*
-
Pedigree
-
Phenotype
-
RNA Splice Sites / genetics
-
Sequence Deletion / genetics*
Substances
-
FLNA protein, human
-
Filamins
-
RNA Splice Sites
Supplementary concepts
-
Cardiac valvular dysplasia, X-linked