TY - JOUR
T1 - Frontometaphyseal dysplasia
T2 - mutations in FLNA and phenotypic diversity
AU - Robertson, Stephen P
AU - Jenkins, Zandra A
AU - Morgan, Timothy
AU - Adès, Lesley
AU - Aftimos, Salim
AU - Boute, Odile
AU - Fiskerstrand, Torunn
AU - Garcia-Miñaur, Sixto
AU - Grix, Arthur
AU - Green, Andrew
AU - Der Kaloustian, Vazken
AU - Lewkonia, Ray
AU - McInnes, Brenda
AU - van Haelst, Mieke M
AU - Mancini, Grazia
AU - Macini, Grazia
AU - Illés, Tamás
AU - Mortier, Geert
AU - Newbury-Ecob, Ruth
AU - Nicholson, Linda
AU - Scott, Charles I
AU - Ochman, Karolina
AU - Brozek, Izabela
AU - Shears, Deborah J
AU - Superti-Furga, Andrea
AU - Suri, Mohnish
AU - Whiteford, Margo
AU - Wilkie, Andrew O M
AU - Krakow, Deborah
PY - 2006/8/15
Y1 - 2006/8/15
N2 - 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.
AB - 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.
KW - Adult
KW - Child, Preschool
KW - Cohort Studies
KW - Contractile Proteins/genetics
KW - Female
KW - Filamins
KW - Genes, X-Linked
KW - Genetic Variation
KW - Humans
KW - Magnetic Resonance Imaging
KW - Male
KW - Microfilament Proteins/genetics
KW - Middle Aged
KW - Mutation
KW - Osteochondrodysplasias/diagnosis
KW - Phenotype
KW - Radiography
KW - X Chromosome Inactivation/genetics
U2 - https://doi.org/10.1002/ajmg.a.31322
DO - https://doi.org/10.1002/ajmg.a.31322
M3 - Article
C2 - 16835913
SN - 1552-4825
VL - 140
SP - 1726
EP - 1736
JO - American Journal of Medical Genetics Part A
JF - American Journal of Medical Genetics Part A
IS - 16
ER -