背景:与ALG1相关的糖基化先天性疾病(ALG1-CDG)是一种罕见的常染色体隐性遗传疾病。由于ALG1基因致病变异引起的β1,4甘露糖基转移酶的缺乏,聚糖在蛋白质糖基化途径中的组装和加工受损,导致多器官受累的广泛临床谱。为了提高临床医生对其表现和基因型的认识,我们在此报道了一名ALG1基因新变异的新患者,并回顾了研究基因型-表型相关性的文献.
方法:收集临床特征,和临床外显子组测序用于鉴定致病变异。MutationTaster,PyMol,和FoldX用于预测致病性,蛋白质三维模型分子结构的变化,以及由新颖变体引起的自由能变化。
结果:先证者是一名13个月大的中国汉族男性,以癫痫发作为特征,精神运动发育延迟,肌张力减退,肝脏和心脏受累。临床外显子组测序显示双等位基因化合物杂合性变异,先前报道的变体c.434G>A(p。G145N,父系)和一个新的变体c.314T>A(p。V105N,母亲)。文献综述发现,在严重的表型中,临床表现的发生率明显高于轻度表型,包括先天性肾病综合征,丙种球蛋白血症,和严重的积水。纯合c.773C>T是与严重表型相关的强致病性变体。当c.773C>T为杂合时,具有另一种变体导致强保守区域内氨基酸取代的患者(c.866A>T,c.1025A>C,c.1182C>G)可能比不太保守区域内的那些引起更严重的表型(c.434G>A,c.450C>G,c.765G>A,c.1287T>A)。c.1129A>G,c.1076C>T,和c.1287T>A更可能与轻度表型相关。疾病表型的评估需要基因型和临床表现的组合。
结论:本文报道的病例增加了ALG1-CDG中鉴定的突变,对该文献的回顾扩展了对该疾病的表型和基因型谱的研究。
The congenital disorder of glycosylation associated with ALG1 (ALG1-CDG) is a rare autosomal recessive disease. Due to the deficiency of β1,4 mannosyltransferase caused by pathogenic variants in ALG1 gene, the assembly and processing of glycans in the protein glycosylation pathway are impaired, resulting in a broad clinical spectrum with multi-organ involvement. To raise awareness of clinicians for its manifestations and genotype, we here reported a new patient with a novel variant in ALG1 gene and reviewed the literature to study the genotype-phenotype correlation.
Clinical characteristics were collected, and clinical exome sequencing was used to identify the causative variants. MutationTaster, PyMol, and FoldX were used to predict the pathogenicity, changes in 3D model molecular structure of protein, and changes of free energy caused by novel variants.
The proband was a 13-month-old Chinese Han male characterized by epileptic seizures, psychomotor development delay, muscular hypotonia, liver and cardiac involvement. Clinical exome sequencing revealed the biallelic compound heterozygosity variants, a previously reported variant c.434G>A (p.G145N, paternal) and a novel variant c.314T>A (p.V105N, maternal). The literature review found that in severe phenotypes, the incidences of clinical manifestations were significantly higher than that in mild phenotypes, including congenital nephrotic syndrome, agammaglobulinemia, and severe hydrops. Homozygous c.773C>T was a strongly pathogenic variant associated with a severe phenotype. When heterozygous for c.773C>T, patients with another variant leading to substitution in amino acids within the strongly conserved regions (c.866A>T, c.1025A>C, c.1182C>G) may cause a more severe phenotype than those within less-conserved regions (c.434G>A, c.450C>G, c.765G>A, c.1287T>A). c.1129A>G, c.1076C>T, and c.1287T>A were more likely to be associated with a mild phenotype. The assessment of disease phenotypes requires a combination of genotype and clinical manifestations.
The
case reported herein adds to the mutations identified in ALG1-CDG and a review of this literature expands the study of the phenotypic and genotypic spectrum of this disorder.