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Exon skip-inducing variants in FLNA in an attenuated form of frontometaphyseal dysplasia.
- Source :
-
American journal of medical genetics. Part A [Am J Med Genet A] 2021 Dec; Vol. 185 (12), pp. 3675-3682. Date of Electronic Publication: 2021 Jul 17. - Publication Year :
- 2021
-
Abstract
- Pathogenic variation in the X-linked gene FLNA causes a wide range of human developmental phenotypes. Loss-of-function is usually male embryonic-lethal, and most commonly results in a neuronal migration disorder in affected females. Gain-of-function variants cause a spectrum of skeletal dysplasias that present with variable additional, often distinctive, soft-tissue anomalies in males and females. Here we present two, unrelated, male individuals with novel, intronic variants in FLNA that are predicted to be pathogenic. Their phenotypes are reminiscent of the gain-of-function spectrum without the skeletal manifestations. Most strikingly, they manifest urethral anomalies, cardiac malformations, and keloid scarring, all commonly encountered features of frontometaphyseal dysplasia. Both variants prevent inclusion of exon 40 into the FLNA transcript, predicting the in-frame deletion of 42 amino acids, however the abundance of FLNA protein was equivalent to that observed in healthy individuals. Loss of these 42 amino acids removes sites that mediate key FLNA functions, including binding of some ligands and phosphorylation. This phenotype further expands the spectrum of the FLNA filaminopathies.<br /> (© 2021 Wiley Periodicals LLC.)
- Subjects :
- Child
Cicatrix complications
Cicatrix genetics
Cicatrix physiopathology
Exons genetics
Forehead physiopathology
Genes, X-Linked
Genetic Diseases, X-Linked physiopathology
Genetic Variation genetics
Humans
Infant
Keloid complications
Keloid genetics
Keloid physiopathology
Loss of Function Mutation genetics
Male
Mutation genetics
Osteochondrodysplasias physiopathology
Pedigree
Phenotype
Phosphorylation genetics
Urethra abnormalities
Urethra physiopathology
Filamins genetics
Forehead abnormalities
Genetic Diseases, X-Linked genetics
Genetic Predisposition to Disease
Osteochondrodysplasias genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4833
- Volume :
- 185
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- American journal of medical genetics. Part A
- Publication Type :
- Academic Journal
- Accession number :
- 34272929
- Full Text :
- https://doi.org/10.1002/ajmg.a.62424