Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients.
Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients.
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DOI：
10.1186/s13023-021-02151-2
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发表时间：
2021-12-20
影响因子：
3.7
通讯作者：
Wattanasirichaigoon D
中科院分区：
文献类型：
--
作者：
Phetthong T;Tim-Aroon T;Khongkraparn A;Noojarern S;Kuptanon C;Wichajarn K;Sathienkijkanchai A;Suphapeetiporn K;Charoenkwan P;Tantiworawit A;Noentong N;Wattanasirichaigoon D
戈谢病（GD）是一种罕见的溶酶体贮积症，以肝脾肿大和全血细胞减少为特征，伴或不伴神经系统受累。该疾病分为三种表型：GD 1型或非神经元病性GD; GD 2型或急性神经元病性GD;和GD 3型或慢性神经元病性GD。本研究的目的是描述2010-2018年期间诊断和/或随访的泰国GD患者的临床特征，并进行重新基因分型，包括分析之前未在泰国患者中研究的GBA重组等位基因。来自7个医疗中心的27名患者参加了这项研究。所有病例均为儿童发病。GD 3（44.5%）是最常见的表型，其次是GD 2（40.7%）和GD 1（14.8%），其中1例为新生儿GD。GD 1、GD 2和GD 3的中位发病年龄分别为72、4和12个月，表明泰国患者的GD 1和GD 3发病相对较早。所有GD 1患者和大多数GD 3患者均接受了ERT。4例GD 3患者接受了ERT，随后接受了HSCT。未接受或延迟接受ERT的GD 3患者显示不利结局。我们鉴定了14种变异体，包括两种新的（p.S384F和p.W533*）和12种已报道的致病性变异体：p.L483P、p.N409S、p.R159W、p.P305A、p.A175G、p.D448H、p.V414L、IVS 2 +1G>A、IVS 6 -1G>C、IVS 7 +1G>C、IVS 9 -3C>G和Rec 1a。p.L483P是本研究中发现的最常见的等位基因，占66%（33/50个等位基因），其次是IVS 2 +1G>A、Rec 1a和IVS 6 -1G>C。24%的患者被重新分配了经验证的基因型，其中大多数（6例中的4例）为GD 2患者。在新生儿GD患者中发现[p.S384F + p.W533*]与p.L483P复合，表明p.S384F可增强p.W533* 的有害作用，反之亦然。神经病性GD在泰国受影响人群中非常普遍。纯合子p.L483P是泰国患者中最常见的基因型。重组等位基因Rec 1a和剪接突变与GD 2和GD 3的严重病例相关。突变谱可用于设计逐步分子分析、群体遗传筛查和神经病性GD的新治疗研究。在线版本包含补充材料，可通过10.1186/s13023-021-02151-2获得。
Gaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010–2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD. The online version contains supplementary material available at 10.1186/s13023-021-02151-2.
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