Centre for Human Genetics, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.
J Med Genet. 2010 Feb;47(2):103-11. doi: 10.1136/jmg.2008.065888. Epub 2009 Jul 6.
The 10q24 chromosomal region has previously been implicated in split hand foot malformation (SHFM). SHFM3 was mapped to a large interval on chromosome 10q. The corresponding dactylaplasia mouse model was linked to the syntenic locus on chromosome 19. It was shown that the two existing Dac alleles result from MusD-insertions upstream of or within Dactylin (Fbxw4). However, all efforts to find the underlying cause for the human SHFM3 have failed on the analysis of all the genes within the linkage region. Intriguingly a submicroscopic duplication within the critical locus on chromosome 10q24 was associated with the phenotype.
As a part of screening for genomic rearrangements in cases with unexplained syndromic limb defects, a cohort of patients was analysed by array comparative genomic hybridisation (CGH). A 10q24 microduplication was detected in two individuals with distal limb deficiencies associated with micrognathia, hearing problems and renal hypoplasia. In addition, in a family with two affected siblings, a somatic/gonadal mosaicism for the microduplication was detected in the apparently healthy mother. Using a high resolution oligoarray further delineation of the duplication size was performed.
The detected 10q24 genomic imbalance in our syndromic patients has a similar size to the duplication in the previously reported individuals with an isolated form of SHFM, thus extending the clinical spectrum of SHFM3. These findings clearly demonstrate the importance of array CGH in the detection of the aetiology of complex, clinically heterogeneous entities.
10q24 染色体区域先前与分裂手足畸形（SHFM）有关。SHFM3 被映射到染色体 10q 上的一个大区间。相应的指骨缺失小鼠模型与染色体 19 上的同源基因座相连。结果表明，两个现有的 Dac 等位基因是由于 MusD 在上游或 Dactylin（Fbxw4）内插入引起的。然而，在分析连锁区域内的所有基因时，所有试图找到人类 SHFM3 根本原因的努力都失败了。有趣的是，在染色体 10q24 的关键基因座内发现了亚微重复与表型有关。
作为不明原因的综合征性肢体缺陷病例中基因组重排筛选的一部分，通过阵列比较基因组杂交（CGH）分析了一组患者。在两个伴有小颌畸形、听力问题和肾发育不全的远端肢体缺陷患者中检测到 10q24 微重复。此外，在一个有两个受影响兄弟姐妹的家庭中，在看似健康的母亲中检测到微重复的体/性腺镶嵌现象。使用高分辨率寡核苷酸微阵列进一步确定了重复的大小。
我们在综合征患者中检测到的 10q24 基因组不平衡与先前报道的孤立性 SHFM 个体中的重复具有相似的大小，从而扩展了 SHFM3 的临床谱。这些发现清楚地表明了阵列 CGH 在检测复杂、临床异质性实体病因中的重要性。
