Identification of a novel insertion mutation in FGFR3 that causes thanatophoric dysplasia type 1

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 domi...

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Bibliographic Details
Published in:American journal of medical genetics. Part A 2016-06, Vol.170A (6), p.1573-1579
Main Authors: Lindy, Amanda S., Basehore, Monica J., Munisha, Mumingjiang, Williams, Aimee Leanne, Friez, Michael J., Writzl, Karin, Willems, Patrick, Dougan, Scott T.
Format: Article
Language:English
Subjects:
Abortion, Induced
Alleles
Animals
Autopsy
Danio rerio
Exons
Female
Fetus
fibroblast growth factor receptor
Gene Expression
Genetic Association Studies
Genotype
Humans
insertion mutation
Mutagenesis, Insertional
Mutation
neonatal dwarfism
Phenotype
Pregnancy
prenatal diagnosis
Receptor, Fibroblast Growth Factor, Type 3 - deficiency
Receptor, Fibroblast Growth Factor, Type 3 - genetics
thanatophoric dysplasia
Thanatophoric Dysplasia - diagnosis
Thanatophoric Dysplasia - genetics
Zebrafish
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Summary: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.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.37609