一例TRAPPC9复合杂合变异导致的智力发育迟缓患儿的诊断

Diagnosis of a case with mental retardation due to novel compound heterozygous variants of TRAPPC9 gene

目的分析一例智力发育迟缓患儿的遗传学病因,并对患儿进行确诊.方法收集患儿的临床资料,采集患者和正常表型亲代的外周血样提取基因组DNA.应用高通量测序法筛查、Sanger测序法验证TRAPPC9基因变异位点.通过蛋白质预测软件预测、相关数据库和PubMed文献检索变异位点的致病性.结合患者临床表现和相关检查结果,根据《遗传变异分类标准与指南》判断该基因变异的致病性.结果患儿智力发育迟缓、语言发育迟缓、自理能力差;脑部成像显示脑沟裂增宽、蛛网膜下腔增宽、胼胝体压部发育不良等.测序发现患儿存在TRAPPC9基因c.1705T>C(p.S569P)、c.1708dupC(p.R570Pfs*80)和c.2273delA(p.N758Tfs*22)杂合变异.患儿母亲为TRAPPC9基因c.1705T>C(p.S569P)和c.1708dupC(p.R570Pfs*80)杂合变异携带者,患者父亲为TRAPPC9基因c.2273delA(p.N758Tfs*22)杂合变异携带者.结论TRAPPC9基因c.1708dupC(p.R570Pfs*80)和c.2273delA(p.N758Tfs*22)复合杂合变异可能是该智力发育迟缓患儿的致病原因.该复合杂合变异未见文献报道,是智力发育迟缓13型的新致病变异.由于智力发育迟缓临床表现及遗传的异质性,针对性的基因检测对先天性发育迟缓的精确诊断具有重要的意义.

Objective To explore the genetic basis for a boy with mental retardation.Methods Clinical data and peripheral blood samples of the family were collected.Potential variants were screened by using a panel for genes associated with intellectual impairment.Suspected variants were verified by PCR and Sanger sequencing.Results The child presented with mental retardation,language delay and poor self-care.Imaging analysis showed widening of brain fissures and subarachnoid space,and dysplasia of corpus callosum.Three novel heterozygous variants,namely c.1705T>C(p.S569P),c.1708dupC(p.R570Pfs*80)and c.2273delA(p.N758Tfs*22),were identified in the TRAPPC9 gene.The mother of the proband has carried the c.1708dupC(p.R570Pfs*80)and c.1705T>C(p.S569P)variants,while his father has carried the c.2273delA(p.N758Tfs*22)variant.Conclusion The compound heterozygous variants of the TRAPPC9 gene probably underlie the disease in this family.Considering the clinical and genetic heterogeneity of mental retardation,genetic testing is essential for attaining diagnosis for patients with the relevant phenotype.