摘要目的:探讨一个Canavan病家系的遗传学病因，并为其提供产前诊断。方法:对先证者进行全外显子组测序及生物信息学分析。用Sanger测序法对候选变异进行验证，并对产前绒毛样本进行检测。结果:患儿为女性，生后4个月出现嗜睡、肌张力低、双眼无神、尿N-乙酰天冬氨酸升高。头颅磁共振成像示髓鞘化异常，颅内多个大片状异常信号。全外显子组测序显示患儿携带 ASPA基因的复合杂合变异，包括第1外显子的c.187A>G(p.Arg63Gly)和第4外显子的c.634+1G>A(p.？)。Sanger测序证实二者分别遗传自母亲和父亲，其表型正常的哥哥携带c.634+1G>A(p.？)杂合变异，下一胎产前绒毛检查提示胎儿携带c.187A>G(p.Arg63Gly)杂合变异。 结论:全外显子组测序可以用于诊断Canavan病。 ASPA基因的复合杂合变异可能为该家系的遗传学病因。

abstractsObjective:To explore the genetic basis for a Chinese patient suspected for Canavan disease.Methods:Whole exome sequencing (WES) was carried out for the proband, and candidate variants were verified by Sanger sequencing of the proband, her parents and brother. Prenatal diagnosis was provided to her mother by chorionic villi sampling (CVS) upon her subsequent pregnancy.Results:The proband, a 4-month-old female infant, had manifested drowsiness, hypotonia and apathy. Urine metabolism screening showed elevated N-acetylaspartic acid. Cranial magnetic resonance imaging revealed abnormal myelination and multiple abnormal signals in large brain areas. WES revealed that the proband has harbored compound heterozygous variants of the ASPA gene, namely c. 187A>G (p.Arg63Gly) in exon 1 and c. 634+ 1G>A (P.? ) in exon 4. Sanger sequencing confirmed that the c. 187A>G (p.Arg63Gly) and c. 634+ 1G>A (p.? ) variants were respectively inherited from her mother and father. Her phenotypically normal brother has carried a heterozygous c. 634+ 1G>A (p.? ) variant. Prenatal diagnosis by CVS indicated that the fetus was a heterozygous carrier of the c. 187A>G variant. Conclusion:WES can facilitate the diagnosis of Canavan disease, particularly for those lacking specific phenotypes of the disease. The compound heterozygous variants of the ASPA gene probably underlay the Canavan disease in this patient, and the result has enabled prenatal diagnosis for this family.