CHD8基因新发突变的孤独症谱系障碍1例报道并文献复习

A novel CHD8 gene mutation in a patient with autism spectrum disorder and literature review

目的提高对孤独症谱系障碍(ASD)CHD8基因突变患儿临床表型和基因型的认识。方法回顾性分析1例存在CHD8基因突变的ASD患儿的临床资料,并文献复习。结果 1男,3岁3月龄,头围55.0 cm(>4 s),身高107.0 cm(>2 s),体重23.5 kg(>2 s)。有典型的ASD表现,运动明显落后,有慢性便秘史。2提取患儿及其父母静脉血DNA,以二代高通量测序技术对4 813个临床相关基因的外显子区进行测序,共检测到变异8 982个,经筛选流程筛选ASD相关的EHMT1、PCDH9、NLGN4X的错义突变,CHD8的无义突变(c.307C>T,p.Gln103*)有致病可能。Sanger测序显示患儿EHMT1、PCDH9的突变来源于父亲,NLGN4X的突变来源于母亲,患儿父母未发现CHD8的突变。3目前国外共报道了CHD8基因与神经发育障碍有关的15个重要突变;CHD8基因突变患者的临床表型包括ASD表现(87%)、身材高大(86%)、大头畸形(80%)、慢性便秘或间歇性腹泻(80%)、运动落后(67%)和睡眠异常(67%)等,本文病例临床表型与文献报道较为一致。结论 CHD8基因是ASD重要的易感基因;ASD患儿合并大头畸形、生长过快,且有慢性便秘或间歇性腹泻时应考虑CHD8基因突变可能,可行基因检测协助诊断。

Objective To draw attention to the phenotype and genotype of patients with autism spectrum disorders（ ASD）carrying CHD8 mutation. Methods The clinical data of one patient with ASD carrying CHD8 mutation, including clinical manifestations,laboratory findings,genetic testing results and family investigation were summarized and analyzed,and relevant literatures about CHD8 mutation were reviewed in this article. Results 1 The 3-year-and-3-month boy was presented with macrocephaly（ head circumference was 55. 0 cm,Z〉4 s）,overgrowth（ height was 107. 0 cm,Z〉2 s; weight was 23. 5 kg,Z〉2 s）and typical autistic behavior as well as significant motor delay and gastrointestinal（ GI） problems（ chronic constipation）. No additional patient was found in his family. 2 Targeting 4 813 genes associated with known clinical phenotypes,a total of 8 982 variances were found in the patient via next-generation high-throughput DNA sequencing. Missense mutations of autism-related genes EHMT1,PCDH9,NLGN4 X and nonsense mutation of CHD8 [c. 307 C 〉T,p. Gln103 ＊（ NM_020920. 3） ] were probably pathogenic after filtering unrelated variances. EHMT1,PCDH9 mutations were identified in his father and NLGN4 X mutation in his mother,but CHD8 mutation was not identified in his parents via Sanger sequencing. 3To date a total of 15 independent CHD8 mutations associated with neurodevelopmental disorders has been reported worldwide. Common phenotypic features of patients with CHD8 disruptions include autism（ 87%）,overgrowth（ 86%）,macrocephaly（ 80%）,GI complaints（ 80%）,motor delay（ 67%,especially fine motor coordination） and sleep problems（ 67%）. Conclusion The mutation of CHD8 is an important risk factor of ASD. ASD patients with macrocephaly,overgrowth and GI problems should be considered as carrying CHD8 mutation and genetic testing is recommended to confirm the diagnosis.