黏多糖贮积症ⅢA型一个家系的遗传学分析

Genetic analysis of a Chinese pedigree affected with Mucopolysaccharidosis typeⅢA

目的探讨1例以肥厚型心肌病为首发表现的黏多糖贮积症ⅢA型(MSPⅢA)患者的临床及遗传学特征。方法选取2022年1月就诊于济宁医学院附属医院的1例MPSⅢA先证者及其家系成员(3代共7人)作为研究对象。收集先证者的临床资料,采集先证者及其家系成员的外周血样,进行全外显子组测序,对候选变异进行Sanger测序家系验证。同时根据变异位点的相关疾病进行硫酸乙酰肝素硫酸酯酶的活性检测。结果先证者为49岁女性,心脏MRI提示左室壁明显增厚,最厚处近20 mm,钆延迟增强扫描心尖部心肌局部延迟强化。全外显子组测序发现患者SGSH基因存在c.545G>A(p.Arg182His)/c.703G>A(p.Asp235Asn)复合杂合变异。Sanger测序提示其母亲携带c.545G>A(p.Arg182His)杂合变异,父亲、姐姐、妹妹和儿子均携带c.703G>A(p.Asp235Asn)杂合变异。依据美国医学遗传学与基因组学学会(ACMG)相关指南,c.545G>A及c.703G>A均评级为致病性变异(PM2_Supporting+PM3+PP1_Strong+PP3+PP4;PS3+PM1+PM2_Supporting+PM3+PP3+PP4)。患者外周血白细胞乙酰肝素-N-硫酸酯酶活性明显偏低,为1.6 nmol/(g·h)。父亲、母亲、姐姐、妹妹和儿子检测均未见异常。结论SGSH基因复合杂合变异可能是先证者MPSⅢA的遗传学病因,心肌肥厚为相关的临床表型。

Objective To explore the clinical and genetic characteristics of a patient with hypertrophic cardiomyopathy as the initial manifestation of Mucopolysaccharidosis typeⅢA(MPSⅢA).Methods A female patient with MPSⅢA who was admitted to the Affiliated Hospital of Jining Medical University in January 2022 and her family members(seven individuals from three generations)were selected as the study subjects.Clinical data of the proband were collected.Peripheral blood samples of the proband was collected and subjected to whole exome sequencing.Candidate variants were verified by Sanger sequencing.Heparan-N-sulfatase activity was determined for the disease associated with the variant site.Results The proband was a 49-year-old woman,for whom cardiac MRI has revealed significant thickening(up to 20 mm)of left ventricular wall and delayed gadolinium enhancement at the apical myocardium.Genetic testing revealed that she has harbored compound heterozygous variants in exon 17 of the SGSH gene,namely c.545G>A(p.Arg182His)and c.703G>A(p.Asp235Asn).Based on guidelines from the American College of Medical Genetics and Genomics(ACMG),both variants were predicted to be pathogenic(PM2_Supporting+PM3+PP1Strong+PP3+PP4;PS3+PM1+PM2_Supporting+PM3+PP3+PP4).Sanger sequencing confirmed that her mother was heterozygous for the c.545G>A(p.Arg182His)variant,whilst her father,sisters and her son were heterozygous for the c.703G>A(p.Asp235Asn)variant.Determination of blood leukocyte heparan-N-sulfatase activity suggested that the patient had a low level of 1.6 nmol/(g·h),whilst that of her father,elder and younger sisters and son were all in the normal range.Conclusion The compound heterozygous variants of the SGSH gene probably underlay the MPSⅢA in this patient,for which hypertrophic cardiomyopathy is an associated phenotype.