Makrythanasis Periklis, Temtamy Samia, Aglan Mona S, Otaify Ghada A, Hamamy Hanan, Antonarakis Stylianos E
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
Hum Mutat. 2014 Aug;35(8):959-63. doi: 10.1002/humu.22597. Epub 2014 Jun 28.
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.
FGFR3基因中报道的大多数突变是显性激活突变，可导致多种短肢骨发育不良，包括软骨发育不全和综合征性颅缝早闭。我们报告了一对表亲父母所生的两兄弟的表型及潜在分子异常。临床表现为身材高大和严重骨骼异常，导致无法行走，伴有屈曲指、蜘蛛指和脊柱侧弯。全外显子组测序显示FGFR3基因第12外显子（NM_000142.4:c.1637C>A: p.(Thr546Lys)）存在纯合的新型错义突变。该变异位于蛋白质的激酶结构域，预计具有致病性。它位于已知的软骨发育不全热点区域附近。这是人类中FGFR3纯合功能丧失突变导致骨骼过度生长综合征的首例报道。
