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Abstract：
Background: Split-hand/foot malformation type 1 (SHFM1) refers to the group of rare congenital limb disorders defined by the absence or hypoplasia of the central rays of the autopods with or without accompanying anomalies, such as hearing loss, craniofacial malformation, and ectodermal dysplasia. Consequently, the condition is characterized by clinical variability that hinders diagnostic and counseling procedures. SHFM1 is caused by pathogenic variants affecting the DLX5/6 genes and/or their tissue-specific enhancers at the 7q21.3 locus. Herein, we report on seven patients from five unrelated Polish families affected by variable symptoms of the SHFM1 spectrum, all harboring 7q21.3 or 7q21.2-q21.3 rearrangements, and provide a genotype-phenotype correlation in the studied cohort. Methods: We applied GTG banding, array-based comparative genomic hybridization (aCGH), and whole-genome sequencing (WGS) in order to identify the causative aberrations in all affected patients. Results: The identified pathogenic structural variants included deletions and/or translocations involving the 7q21.3 locus, i.e., t(7;10)(q21.3;q22.2) and t(7;12)(q21.3;q21.2) in all affected individuals. Interestingly, a sporadic carrier of the latter aberration presented the SHFM1 phenotype with additional features overlapping with Baker-Gordon syndrome (BAGOS), which resulted from the translocation breakpoint at chromosome 12 within the SYT1 gene. Conclusion: Clinical variability of the studied cohort reflects the composition of the DLX5/6 regulatory elements that were dislocated from their target genes by chromosomal rearrangements. The correlation of our data with the previously published observations enabled us to update the phenotypic subregions and regulatory units within the SHFM1 locus. In addition, we present the first case of SHFM1 and BAGOS-like phenotype that resulted from translocation breakpoints at chromosomes 7 and 12, both of which were pathogenic, and consequently, we show the first evidence that BAGOS can also result from the regulatory loss-of-function SYT1 mutations. In this paper, we emphasize the utility of sequence-based approaches in molecular diagnostics of disorders caused by regulatory structural variants.
摘要：
背景：1型手/足分裂畸形（SHFM1）是指一组罕见的先天性肢体疾病，其定义为自体足中央射线的缺失或发育不全，伴有或不伴有异常，比如听力损失,颅面畸形,外胚层发育不良.因此,这种情况的特点是临床变异性，阻碍了诊断和咨询程序。SHFM1由在7q21.3基因座处影响DLX5/6基因和/或其组织特异性增强子的致病变体引起。在这里，我们报告了来自五个不相关的波兰家庭的7名患者，这些患者受到SHFM1谱的不同症状的影响，都有7q21.3或7q21.2-q21.3重新安排，并在研究队列中提供基因型-表型相关性。方法：我们应用GTG显带，基于阵列的比较基因组杂交(aCGH)，和全基因组测序（WGS），以确定所有受影响患者的病因畸变。结果：鉴定的致病性结构变异包括涉及7q21.3基因座的缺失和/或易位，即，所有受影响个体的t(7;10)(q21.3;q22.2)和t(7;12)(q21.3;q21.2)。有趣的是,后者的散发性携带者表现出SHFM1表型，其其他特征与Baker-Gordon综合征（BAGOS）重叠，这是由SYT1基因内12号染色体的易位断裂点引起的。结论：研究队列的临床变异性反映了DLX5/6调控元件的组成，这些元件通过染色体重排从其靶基因脱位。我们的数据与先前发表的观察结果的相关性使我们能够更新SHFM1基因座内的表型亚区和调控单元。此外,我们介绍了第一例SHFM1和BAGOS样表型是由7号和12号染色体易位断点引起的，因此，我们显示了第一个证据,即BAGOS也可以由调节功能丧失SYT1突变引起.在本文中,我们强调基于序列的方法在由调节性结构变异引起的疾病的分子诊断中的实用性.
