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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.

Author information

1
Department of Neurogenetics, GeneDx, Gaithersburg, Maryland.
2
Greenwood Genetic Center, Greenwood, South Carolina.
3
Department of Cellular Biology, University of Georgia, Athens, Georgia.
4
Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia.
5
GENDIA, Antwerp, Belgium.

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.

KEYWORDS:

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

PMID:
27028100
DOI:
10.1002/ajmg.a.37609
[Indexed for MEDLINE]

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