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A Novel Homozygous Mutation in FGFR 3 Causes Tall Stature, Severe Lateral Tibial Deviation, Scoliosis, Hearing Impairment, Camptodactyly, and Arachnodactyly
Author(s) -
Makrythanasis Periklis,
Temtamy Samia,
Aglan Mona S.,
Otaify Ghada A.,
Hamamy Hanan,
Antonarakis Stylianos E.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22597
Subject(s) - arachnodactyly , achondroplasia , camptodactyly , missense mutation , biology , short stature , craniosynostosis , scoliosis , genetics , exon , fibroblast growth factor receptor 3 , mutation , gene , endocrinology , medicine , marfan syndrome , fibroblast growth factor , receptor
Most reported mutations in the FGFR 3 gene are dominant activating mutations that cause a variety of short‐limbed bone dysplasias including achondroplasia and syndromic craniosynostosis. We report the phenotype and underlying molecular abnormality in two brothers, born to first cousin parents. The clinical picture is characterized by tall stature and severe skeletal abnormalities leading to inability to walk, with camptodactyly, arachnodactyly, and scoliosis. Whole exome sequencing revealed a homozygous novel missense mutation in the FGFR 3 gene in exon 12 (NM_000142.4:c.1637C>A: p.(Thr546Lys)). The variant is found in the kinase domain of the protein and is predicted to be pathogenic. It is located near a known hotspot for hypochondroplasia. This is the first report of a homozygous loss‐of‐function mutation in FGFR 3 in human that results in a skeletal overgrowth syndrome.