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Frontometaphyseal dysplasia: Mutations in FLNA and phenotypic diversity
Author(s) -
Robertson Stephen P.,
Jenkins Zandra A.,
Morgan Timothy,
Adès Lesley,
Aftimos Salim,
Boute Odile,
Fiskerstrand Torunn,
GarciaMiñaur Sixto,
Grix Arthur,
Green Andrew,
Kaloustian Vazken Der,
Lewkonia Ray,
McInnes Brenda,
van Haelst Mieke M.,
Macini Grazia,
Illés Tamás,
Mortier Geert,
NewburyEcob Ruth,
Nicholson Linda,
Scott Charles I.,
Ochman Karolina,
Brożek Izabela,
Shears Deborah J.,
SupertiFurga Andrea,
Suri Mohnish,
Whiteford Margo,
Wilkie Andrew O.M.,
Krakow Deborah
Publication year - 2006
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.31322
Subject(s) - flna , filamin , missense mutation , genetics , biology , phenotype , proband , dysplasia , mutation , gene , cytoskeleton , cell
Frontometaphyseal dysplasia is an X‐linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X‐linked gene, FLNA . We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin‐binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X‐inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder. © 2006 Wiley‐Liss, Inc.