A Novel SLC20A2 Mutation Associated with Familial Idiopathic Basal Ganglia Calcification and Analysis of the Genotype-Phenotype Association in Chinese Patients Translated title: SLC20A2基因突变相关家族性特发性基底节钙化新位点报道及中国患者不同基因型导致的特发性基底节钙化临床特点分析

Abstract

Background:

Idiopathic basal ganglia calcification (IBGC) is a genetic disorder characterized by bilateral basal ganglia calcification and neural degeneration. In this study, we reported a new SLC2OA2 mutation of IBGC and reviewed relevant literature to explore the association between phenotypes and genotypes in Chinese IBGC patients.

Methods:

Clinical information of the proband and her relatives were collected comprehensively. Blood samples of both the patient and her father were obtained, and genetic screening related to IBGC was performed using second generation sequencing with their consent. Findings were confirmed by Sanger sequencing. Polyphen-2 was used to predict the potential association between mutations and disease. Then, we retrieved literatures of Chinese IBGC patients and explored the association between phenotype and genotype.

Results:

A novel mutation was identified through genetic testing, and it is suggested to be a damage mutation predicted by Polyphen-2. Through literature review, we found that SLC20A2 mutation is the most common cause for IBGC in China. Its hot spot regions are mainly on the 1 ^st and 8 ^th exons; the second common one is PDGFB where the hot spot covered a length of 220–230 bp localized on the 2 ^nd exon; moreover, Chinese IBGC patients featured early-onset, more severe movement disorder and relatively mild cognitive impairment compared with those in other countries.

Conclusions:

There is significant heterogeneity both in phenotype and genotype in Chinese IBGC patients. Further research of pathogenic mechanism of IBGC is required to eventually develop precise treatment for individuals who suffered this disease.

摘要

背景:

特发性基底节钙化是以双侧基底节钙化和神经系统退行性病变为特征的遗传相关性疾病。本文我们报道了一个SLC20A2相关家族性特发性基底节钙化的新发位点，回顾并总结已经报道的上述各个基因型相关中国患者特发性基底节钙化的临床特点。

方法:

首先，全面收集本家系先证者和家系成员的临床资料，包括病史、实验室检查和诊断相关的影像学资料。在取得相关人员知情同意的前体现，收集先证者和其父亲的外周血标本，并进行特发性基底节钙化相关基因的筛查。基因突变结果在家系内经一代测序验证，与表型共分离，并通过Polyphen-2软件预测极有可能为致病突变。其次，检索已经报道的中国特发性基底节病变的相关报道，总结不同基因型特发性基底节钙化的临床特点。

结果:

通过基因测序、家系内验证和蛋白功能预测，我们发现一个导致特发性基底节钙化的SLC20A2基因新位点。通过分析总结文献，我们发现SLC20A2突变是中国单基因特特发性基底节钙化最常见的原因，其突变热点位于第一和第八号外显子区域。其次是PDGFB基因，

其突变热点位于二号外显子上长度为220-230bp的特定区域。此外，中国特发性基底节钙化的患者多表现为发病年龄早、运动症状较重、认知损害较轻。

结论:

中国特发性基底节钙化患者表型和基因型均存在异质性，但也存在一定共性。在遗传突变基础上进一步机制研究能够帮助我能更清晰的了解疾病的发病机制，从而为不同基因型患者提供个体化治疗。