Glycogen storage disease type III (GSD III) is a rare autosomal recessive inborn error of glycogen degradation pathway due to deficiency or reduced activity of glycogen debranching enzyme (GDE) that results in accumulation of abnormal glycogen in the liver, muscle, and heart. The cardinal hallmarks are hepatomegaly, fasting hypoglycemia, seizures, growth retardation, progressive skeletal myopathy, and cardiomyopathy in few. To date, 258 mutations in amyloglucosidase (AGL) gene have been identified worldwide. However, the mutation spectrum in the Asian Indian region is yet to be well characterized. We investigated 24 patients of Asian origin from 21 unrelated families with a provisional diagnosis of GSD III based on clinical and biochemical criteria. Molecular diagnosis was assessed by bidirectional sequencing and the impact of novel missense variants on the tertiary (three-dimensional) structure of GDE was evaluated by molecular modeling approach. Eighteen different pathogenic variants were identified, out of which 78% were novel. Novel variants included five nonsense, three small duplications and two small deletions, a splice site variant, and three missense variants. Variations in Exons 4, 14, 19, 24, 27, and 33 accounted for 61% of the total pathogenic variants identified and Allele p.Gly798Alafs*3 showed a high allele frequency of 11%. Molecular modeling study of novel pathogenic missense variants indicated the probable underlying molecular mechanism of adverse impact of variations on the structure and catalytic function of human GDE. Our study is the first large study on GSD III from the Asian subcontinent, which further expands the mutation spectrum of AGL.

中文翻译：

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亚洲印度糖原贮积病III型患者的淀粉葡糖苷酶突变谱。

III型糖原贮积病（GSD III）是一种罕见的糖原降解途径的常染色体隐性先天性错误，原因是糖原脱支酶（GDE）缺乏或活性降低，导致肝脏，肌肉和心脏中异常糖原的积累。主要标志是肝肿大，空腹低血糖，癫痫发作，生长迟缓，进行性骨骼肌病和心肌病。迄今为止，全世界已鉴定出淀粉葡糖苷酶（AGL）基因中的258个突变。但是，亚洲印度裔地区的突变谱尚未得到很好的表征。我们根据临床和生化标准调查了来自21个无关家庭的24名亚洲血统患者，并初步诊断出GSD III。通过双向测序评估分子诊断，并通过分子建模方法评估新型错义变体对GDE的三级（三维）结构的影响。鉴定出18种不同的致病变体，其中78％是新颖的。新型变体包括五个废话，三个小重复和两个小缺失，一个剪接位点变体和三个错义变体。外显子4、14、19、24、27和33的变异占已鉴定的全部致病变异的61％，等位基因p.Gly798Alafs * 3的高等位基因频率为11％。新型致病性错义变体的分子模型研究表明，变异可能对人GDE的结构和催化功能产生不利影响的潜在分子机制。