Genetic Analyses Identified a SALL4 Gene Mutation Associated with Holt-Oram Syndrome
Genetic Analyses Identified a SALL4 Gene Mutation Associated with Holt-Oram Syndrome
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遗传分析发现与 Holt-Oram 综合征相关的 SALL4 基因突变
DOI：
10.1089/dna.2017.4094
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发表时间：
2018
影响因子：
3.1
通讯作者：
Wu Yurong
中科院分区：
文献类型：
--
作者：
Li Bojian;Chen Sun;Sun Kun;Xu Rang;Wu Yurong
Holt-Oram综合征（HOS）是一种常染色体显性遗传病，以上肢畸形和先天性心脏缺陷为特征。tbx5基因的改变已被确定为HOS的主要原因，而一些病例不能用tbx5突变来解释。在我们的研究中，我们初步诊断了一名新生儿患有法洛四联症、拇指发育不全、面部发育不良、右耳道畸形为HOS。染色体微阵列分析显示没有病理缺失或重复的染色体片段；全外显子组测序筛选出6个与心脏疾病或综合征相关的候选基因，其中hsall4已被报道为HOS相关基因。我们通过一系列软件对sall4突变位点的致病性进行了评估。结果表明，SALL4-M143V可能是多态性位点，SALL4-R418C可能致病。HOPE和SWISS PDB观察显示，SALL4- r418c导致氨基酸性质的改变，蛋白质氢键的损失，以及SALL4锌指结构域的功能影响。这些结果进一步证实了SALL4-R418C突变体的致病意义。结合遗传分析和生物信息学分析，我们发现asall4基因罕见突变可能与新生儿HOS有关。虽然还有一些疑问需要进一步讨论和探讨，但我们的研究加深了对证候间表型差异和sall4突变在疾病发生中的作用的认识。
Holt–Oram syndrome (HOS) is an autosomal dominant disorder, which is characterized by deformities of upper limbs and congenital heart defects. Alterations ofTBX5gene have been identified to be the leading cause of HOS, while some cases could not be explained byTBX5mutations. In our study, we preliminarily diagnosed a newborn baby, who had Tetralogy of Fallot, thumb agenesis, facial dysplasia, and right ear canal malformation, as HOS. Chromosome microarray analyses showed no pathological deletions or replications of chromosome segments; whole exome sequencing screened out six candidate genes that were involved in cardiac diseases or syndromes among whichSALL4has been reported as HOS related gene. We evaluated the pathogenicity ofSALL4mutant sites by series of software. The results indicated that SALL4-M143V may be a polymorphism site, and SALL4-R418C could cause disease. HOPE and SWISS PDB viewer showed that SALL4-R418C leads to changes in amino acid properties, loss of protein hydrogen bond, and functional impact of SALL4 zinc finger domain. These results further confirmed the pathogenic significance of SALL4-R418C mutant. When genetic analyses coupled with bioinformatic analyses, we identified aSALL4gene rare mutation which might contribute to a newborn with HOS. Although some doubts need to be further discussed and explored, our study deepened the understanding of phenotype difference among syndromes and role ofSALL4mutations in disease occurrence.