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Am J Med Genet A. 2016 Jun;170(6):1573-9. doi: 10.1002/ajmg.a.37609. Epub 2016 Mar 30.

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

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Department of Neurogenetics, GeneDx, Gaithersburg, Maryland.
Greenwood Genetic Center, Greenwood, South Carolina.
Department of Cellular Biology, University of Georgia, Athens, Georgia.
Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia.
GENDIA, Antwerp, Belgium.


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.


fibroblast growth factor receptor; insertion mutation; neonatal dwarfism; prenatal diagnosis; thanatophoric dysplasia; zebrafish

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