Babbs Christian, Heller Raoul, Everman David B, Crocker Mark, Twigg Stephen R F, Schwartz Charles E, Giele Henk, Wilkie Andrew O M
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Hum Genet. 2007 Sep;122(2):191-9. doi: 10.1007/s00439-007-0390-7. Epub 2007 Jun 14.
Split hand/foot malformation (SHFM) with long bone deficiency (SHFLD) is a distinct entity in the spectrum of ectrodactylous limb malformations characterised by associated tibial a/hypoplasia. Pedigrees with multiple individuals affected by SHFLD often include non-penetrant intermediate relatives, making genetic mapping difficult. Here we report a sporadic patient with SHFLD who carries a de novo chromosomal translocation t(2;18)(q14.2;p11.2). Characterisation of the breakpoints revealed that neither disrupts any known gene; however, the chromosome 2 breakpoint lies between GLI2 and INHBB, two genes known to be involved in limb development. To investigate whether mutation of a gene in proximity to the chromosome 2 breakpoint underlies the SHFLD, we sought independent evidence of mutations in GLI2, INHBB and two other genes (RALB and FLJ14816) in 44 unrelated patients with SHFM, SHFLD or isolated long bone deficiency. No convincing pathogenic mutations were found, raising the possibility that a long-range cis acting regulatory element may be disrupted by this translocation. The previous description of a translocation with a 2q14.2 breakpoint associated with ectrodactyly, and the mapping of the ectrodactylous Dominant hemimelia mouse mutation to a region of homologous synteny, suggests that 2q14.2 represents a novel locus for SHFLD.
伴有长骨缺损的裂手/裂足畸形（SHFLD）是肢体缺指/趾畸形谱系中的一种独特病症，其特征为伴有胫骨发育不全或发育不良。常有多个个体患SHFLD的家系中常包含未发病的中间亲属，这使得基因定位变得困难。在此，我们报告了一名散发的SHFLD患者，其携带一个新发的染色体易位t(2;18)(q14.2;p11.2)。对断点的特征分析表明，两者均未破坏任何已知基因；然而，2号染色体断点位于GLI2和INHBB之间，这两个基因已知与肢体发育有关。为了研究靠近2号染色体断点的基因发生突变是否是SHFLD的病因，我们在44名患有SHFM、SHFLD或孤立性长骨缺损的无关患者中寻找GLI2、INHBB以及其他两个基因（RALB和FLJ14816）发生突变的独立证据。未发现令人信服的致病突变，这增加了一种可能性，即这种易位可能破坏了一个远距离顺式作用调节元件。先前有关于与缺指/趾畸形相关的2q14.2断点易位的描述，以及缺指/趾显性半肢畸形小鼠突变映射到同源同线性区域，这表明2q14.2代表了SHFLD的一个新位点。
