title: A novel homozygous mutation in FGFR3 causes tall stature, severe lateral tibial deviation, scoliosis, hearing impairment, camptodactyly, and arachnodactyly.
abstract: Most reported mutations in the FGFR3 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 FGFR3 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 FGFR3 in human that results in a skeletal overgrowth syndrome.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.forename: Mona S
authors.initials: MS
authors.lastname: Aglan
authors.forename: Ghada A
authors.initials: GA
authors.lastname: Otaify
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000293:Adolescent; D054119:Arachnodactyly / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D001827:Body Height; D003241:Consanguinity; D005091:Exons; D015870:Gene Expression; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D012600:Scoliosis / Q000235:genetics* / Q000473:pathology; D016415:Sequence Alignment; D035781:Siblings; D055815:Young Adult
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: FGFR3; exome sequencing; hearing impairment; skeletal dysplasia; tall stature