一例Floating-Harbor综合征患儿的SRCAP基因移码变异分析

Identification of a novel frameshift variant in the SRCAP gene of a child with Floating-Harbor syndrome

目的报道1例由SRCAP基因移码变异所致的Floating-Harbor综合征,并分析SCRAP基因的致病性变异。方法先证者为男性,2岁8月龄,以"发现生长迟缓、语言发育落后2年余"为主要表现。提取患儿及其亲本外周血全基因组DNA,应用全外显子基因测序法检测相关基因变异,并通过Sanger测序验证变异。对可疑的变异进行生物信息学预测分析。结果经全外显子基因测序分析,发现患儿SRCAP基因上第34外显子存在一个c.7273dupA(p.Thr2425Asnfs*18)移码变异,该变异为国内外未经报道的新发变异。通过HomoloGene系统及MEGA软件分析,发现SRCAP蛋白第2425位Thr在哺乳动物、爬行动物乃至无脊椎动物中均高度保守,该氨基酸变异为Asn,可导致编码蛋白在2443位后终止编码,导致编码蛋白完整性严重破坏。同时经PubMed CD-search系统分析,显示SRCAP蛋白在2443位即终止编码,可导致其丧失所有与DNA结合的蛋白基序即AT-hook结构域,从而影响相关目的基因的转录激活,进而导致机体生长发育受影响。另一方面,c.7273dupA(p.Thr2425Asnfs*18)变异经MutationTaster变异预测软件预测,提示该变异为有害变异。结论SRCAP基因c.7273dupA(p.Thr2425Asnfs*18)可能为该患儿罹患Floating-Harbor综合征的病因,致病性变异的检出为临床诊断提供了依据。

Objective To explore the molecular basis for a child featuring with Floating-Harbor syndrome.Methods The 2-year-and-8-month-old child presented with retarded growth and language development.Genomic DNA was extracted from peripheral blood samples from the child and his parents with informed consent and subjected to whole exome sequencing.Suspected variants were verified by Sanger sequencing.Pathogenecity of the variants were predicted by using bioinformatic tools.Results The child was found to carry a de novo frameshift variant c.7273dupA(p.Thr2425Asnfs*18)in the SRCAP gene.The variant was unreported previously and predicted to be pathogenic by MutationTaster.Analysis using HomoloGene system and MEGA software indicated position 2425 of the SRCAP protein to be highly conserved.Substitution of amino acid(Thr)at this position may cause destruction of three AT-hook domains(Amino acid 2857-2869,2936-2948 and 3004-3016)and serious damage to the function of SRCAP protein.Conclusion The patient’s condition may be attributed to the de novo frameshift variant c.7273dupA(p.Thr2425Asnfs*18)of the SRCAP gene.Above finding can facilitate diagnosis of Floating-Harbor syndrome among Chinese population.