Fenwick Aimee L, Goos Jacqueline A C, Rankin Julia, Lord Helen, Lester Tracy, Hoogeboom A Jeannette M, van den Ouweland Ans M W, Wall Steven A, Mathijssen Irene M J, Wilkie Andrew O M
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DS, UK.
BMC Med Genet. 2014 Aug 31;15:95. doi: 10.1186/s12881-014-0095-4.
Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2.
Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis.
These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations.
成纤维细胞生长因子受体2（FGFR2）突变在颅缝早闭的遗传病例中所占比例高于其他任何基因，并且与一系列广泛的临床问题严重程度相关。这些突变中有许多是高度复发性的，其相关特征也有充分记录。克鲁宗综合征通常由FGFR2第三个免疫球蛋白结构域中的杂合错义突变引起。
在此，我们描述了两个家系，每个家系都分离出一种不同的、先前未报道的相同核苷酸的FGFR2突变，即c.1083A>G和c.1083A>T，这两种突变在Pro361密码子处编码一个明显的同义变化。我们提供了实验证据，证明这些突变影响正常的FGFR2剪接，并记录了临床后果，包括轻度克鲁宗综合征表型和颅缝早闭的外显率降低。
这些观察结果增加了影响剪接的FGFR2突变的数量，并为受这些特定突变影响的家系的遗传咨询提供了重要的临床信息。
