title: Clinical and molecular characterization of a Brazilian cohort of campomelic dysplasia patients, and identification of seven new SOX9 mutations.
abstract: Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil . ; Departamento de Genética, Universidade Federal de Rio Grande do Sul, Porto Alegre, RS, Brazil .
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: Mattos
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil .
authors.forename: Maria Teresa V
authors.initials: MT
authors.lastname: Sanseverino
authors.affiliation: Faculdade de Medicina, Universidade Federal de Rio Grande do Sul, Porto Alegre, RS, Brazil .
authors.forename: José Antônio A
authors.initials: JA
authors.lastname: Magalhães
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil .
authors.forename: Júlio César L
authors.initials: JC
authors.lastname: Leite
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil .
authors.forename: Temis Maria
authors.initials: TM
authors.lastname: Félix
authors.affiliation: Faculdade de Medicina, Universidade Federal de Rio Grande do Sul, Porto Alegre, RS, Brazil .
authors.forename: Luiz Alberto
authors.initials: LA
authors.lastname: Todeschini
authors.affiliation: Grupo de Displasias Esqueléticas, Departamento de Genética Médica, Faculdade de Medicina, Universidade Estadual de Campinas, Campinas, SP, Brazil .
authors.forename: Denise P
authors.initials: DP
authors.lastname: Cavalcanti
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil . ; Departamento de Genética, Universidade Federal de Rio Grande do Sul, Porto Alegre, RS, Brazil .
authors.forename: Lavinia
authors.initials: L
authors.lastname: Schüler-Faccini
keywords: SOX9; campomelic dysplasia; osteochondrodysplasias; prenatal diagnosis; skeletal dysplasia