Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity.
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.
Robertson
Stephen P
SP
Department of Paediatrics and Child Health, Dunedin School of Medicine, Dunedin, New Zealand. stephen.robertson@stonebow.otago.ac.nz
Jenkins
Zandra A
ZA
Morgan
Timothy
T
Adès
Lesley
L
Aftimos
Salim
S
Boute
Odile
O
Fiskerstrand
Torunn
T
Garcia-Miñaur
Sixto
S
Grix
Arthur
A
Green
Andrew
A
Der Kaloustian
Vazken
V
Lewkonia
Ray
R
McInnes
Brenda
B
van Haelst
Mieke M
MM
Mancini
Grazia
G
Macini
Grazia
G
Illés
Tamás
T
Mortier
Geert
G
Newbury-Ecob
Ruth
R
Nicholson
Linda
L
Scott
Charles I
CI
Ochman
Karolina
K
Brozek
Izabela
I
Shears
Deborah J
DJ
Superti-Furga
Andrea
A
Suri
Mohnish
M
Whiteford
Margo
M
Wilkie
Andrew O M
AO
Krakow
Deborah
D
D000328:Adult; D002675:Child, Preschool; D015331:Cohort Studies; D003285:Contractile Proteins / Q000235:genetics*; D005260:Female; D064448:Filamins; D050172:Genes, X-Linked; D014644:Genetic Variation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011859:Radiography; D049951:X Chromosome Inactivation / Q000235:genetics
D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins