伴皮层下囊肿的巨脑性白质脑病GLIALCAM突变患者临床遗传学及影像学研究

Abstract

目的分析GLIALCAM突变伴皮层下囊肿的巨脑性白质脑病(megalencephalic leukoencephalopathy with subcortical cysts,MLC)患儿临床遗传学及头颅影像学特征,为准确的遗传咨询和产前诊断打下基础。方法收集6例MLC先证者及家系临床资料,评估患儿头颅MRI,靶向捕获二代测序行GLIALCAM突变检测,分析影像学特征与基因型关系。结果患儿多具有巨颅及典型MLC头颅MRI改变,伴智力运动发育迟缓、倒退及孤独症样行为,临床诊断MLC。6例患儿发现4个错义突变,c. 274C> T(p. Arg92Trp),c. 275G> C(p. Arg92Pro),c. 203A> T(p. Lys68Met)和c. 395C> A(p. Thr132Asn),其中c. 275G> C(p. Arg92Pro)为未报道新突变,5例患儿为杂合突变,1例患儿复合杂合突变,Pt2-Pt5突变遗传自母亲,Pt6遗传自表型正常的父母。5例患儿均出现大脑皮层下白质弥漫性异常信号伴肿胀,1例患儿出现好转。结论 GLIALCAM突变MLC患者多具有巨颅和典型头颅MRI表现,GLIALCAM突变显性遗传患者头颅MRI具有异质性,部分患儿头颅MRI可恢复正常。发现了c. 275G> C(p. Arg92Pro)新突变,扩展了GLIALCAM突变谱,为准确的遗传咨询和产前诊断提供了依据。

Objective To reveal the clinical and genetic characteristics and cranial MRI of megalencephalic leukoencephalopathy with subcortical cysts( MLC) patients with GLIALCAM mutations,and to provide a possibility of accurate genetic counseling and prenatal diagnosis. Methods Clinical information and peripheral venous bloods were collected from 6 families. Quantitative assessment of MRI and genetic analysis were performed through Sanger-sequencing of GLIALCAM. Relationships between genotype and phenotype including cranial MRI of patients were analyzed. Results Six patients were clinically diagnosed with MLC. Clinical characteristics presented as macrocephaly and typical cranial MRI of MLC,with delayed motor and cognitive development,retrogression and autistic behavior.Six patients were genetically diagnosed. Four GLIALCAM mutations c. 274 C > T( p. Arg92 Trp),c. 275 G > C( p. Arg92 Pro),c. 203 A >T( p. Lys68 Met) and c. 395 C > A( p. Thr132 Asn) were detected,including one novel mutation[c. 275 C > G( p. Arg92 Pro) ]. GLIALCAM mutation in one patient was compound heterozygous,and the mutations of the other 5 patients were heterozygous. GLIALCAM mutations of Pt2,Pt3,Pt4,Pt5 were inherited from their mother,and Pt6 inherited mutations from her healthy parents. Subcortical white matter involvement were detected in the MRI of 5 patients,and an improvement in MRI was found in one patient( Pt3). Conclusion Macrocephaly and typical cranial MRI are found in most patients with GLIALCAM mutations. The cranial MRI of patients with GLIALCAM mutations with autosomal dominant inheritance are heterogeneous,and MRI of some patients can return to normal. One novel GLIALCAM mutation is detected in this research,expanding the spectrum of GLIALCAM mutations. This research will provide genetic counseling and prenatal diagnosis for MLC patients' families.