title: Identification of a novel insertion mutation in FGFR3 that causes thanatophoric dysplasia type 1.
abstract: Thanatophoric dysplasia is a type of short-limbed neonatal dwarfism that is usually lethal in the perinatal period. It is characterized by short limbs, a narrow, bell-shaped thorax, macrocephaly with a prominent forehead, and flattened vertebral bodies. These malformations result from autosomal dominant mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. In this report, we describe a novel FGFR3 insertion mutation in a fetus with shortened limbs, curved femurs, and a narrow thorax. The diagnosis of thanatophoric dysplasia type 1 was suspected clinically, and FGFR3 sequencing showed a c.742_743insTGT variant, which predicts p.R248delinsLC. In vivo studies in zebrafish demonstrated that this mutation resulted in the overexpression of zebrafish Fgfr3, leading to the over-activation of downstream signaling and dorsalized embryos. To date, no insertions or deletions in FGFR3 have been reported to cause thanatophoric dysplasia types 1 or 2; therefore, this represents the first report to describe such a mutation. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Neurogenetics, GeneDx, Gaithersburg, Maryland.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Lindy
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina.
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Basehore
authors.affiliation: Department of Cellular Biology, University of Georgia, Athens, Georgia.
authors.forename: Mumingjiang
authors.initials: M
authors.lastname: Munisha
authors.affiliation: Department of Cellular Biology, University of Georgia, Athens, Georgia.
authors.forename: Aimee Leanne
authors.initials: AL
authors.lastname: Williams
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Friez
authors.affiliation: Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors.forename: Karin
authors.initials: K
authors.lastname: Writzl
authors.affiliation: GENDIA, Antwerp, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Willems
authors.affiliation: Department of Cellular Biology, University of Georgia, Athens, Georgia.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Dougan
mesh_terms: D000028:Abortion, Induced; D000483:Alleles; D000818:Animals; D001344:Autopsy; D005091:Exons; D005260:Female; D005333:Fetus; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D016254:Mutagenesis, Insertional; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000172:deficiency* / Q000235:genetics*; D013796:Thanatophoric Dysplasia / Q000175:diagnosis* / Q000235:genetics*; D015027:Zebrafish
chemical_list: D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: fibroblast growth factor receptor; insertion mutation; neonatal dwarfism; prenatal diagnosis; thanatophoric dysplasia; zebrafish