DesRoches Caro-Lyne, Bruun Theodora, Wang Peixiang, Marshall Christian R, Mercimek-Mahmutoglu Saadet
Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1×8, Canada.
Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, M5G 1×8, Canada.
Hum Mutat. 2016 Sep;37(9):926-32. doi: 10.1002/humu.23018. Epub 2016 Jun 27.
Arginine-glycine amidinotransferase (GATM) deficiency is an autosomal-recessive disorder caused by pathogenic variants in GATM. Clinical features include intellectual disability, hypotonia, and myopathy. Due to normal neurodevelopment in asymptomatic individuals on creatine monotherapy, GATM deficiency is a good candidate for newborn screening. To determine the carrier frequency of GATM deficiency, we performed functional characterization of rare missense variants in GATM reported as heterozygous in the Exome Variant Server database. To assess phenotype and genotype correlation, we developed a clinical severity scoring system. Two patients with mild phenotype had a nonsense missense variant. Severe phenotype was present in patients with missense as well as truncating variants. There seems to be no phenotype and genotype correlation. We cloned a novel GATM transcript. We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity. Based on our study results, high Genomic Evolutionary Rate Profiling conservation score, conserved amino acid substitution in species, and low allele frequency in exome databases would be the most sensitive in silico analysis tools to predict pathogenicity of missense variants. We present first study of the functional characterization of missense variants in GATM as well as clinical severity score of patients with GATM deficiency.
精氨酸 - 甘氨酸脒基转移酶（GATM）缺乏症是一种由GATM基因的致病性变异引起的常染色体隐性疾病。临床特征包括智力障碍、肌张力减退和肌病。由于接受肌酸单药治疗的无症状个体神经发育正常，GATM缺乏症是新生儿筛查的理想对象。为了确定GATM缺乏症的携带频率，我们对在外显子变异服务器数据库中报告为杂合子的GATM罕见错义变异进行了功能表征。为了评估表型和基因型的相关性，我们开发了一种临床严重程度评分系统。两名表型轻度的患者有一个无义错义变异。错义变异以及截短变异的患者存在严重表型。似乎不存在表型和基因型的相关性。我们克隆了一种新的GATM转录本。我们发现七个错义变异保留了0%的野生型GATM活性，表明具有潜在致病性。根据我们的研究结果，高基因组进化率谱保守评分、物种中保守的氨基酸替代以及外显子数据库中的低等位基因频率将是预测错义变异致病性最敏感的计算机分析工具。我们首次展示了对GATM错义变异的功能表征以及GATM缺乏症患者的临床严重程度评分的研究。
