Hu Guorui, Zeng Jingxia, Wang Chunli, Zhou Wei, Jia Zhanjun, Yang Jun, Zheng Bixia
Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Department of Emergency/Critical Care Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China.
Front Pediatr. 2020 Mar 27;8:118. doi: 10.3389/fped.2020.00118. eCollection 2020.
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder characterized by a wide range of clinical features, including muscle weakness, hypoglycemia, metabolic acidosis, and multisystem dysfunctions. Loss-of-function mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene are associated with MADD. Disease-causing synonymous variants in the gene have not been reported so far. We reported the clinical course of a Chinese girl who was diagnosed with late-onset MADD by the whole exome sequencing. The effects of variants on mRNA splicing were analyzed through transcript analysis and minigene splice assay . The 6-month-old girl initially showed muscle weakness, muscular hypotonia, mild myogenic damage, and fatty liver. The blood and urine metabolic screening by tandem mass spectrometry suggested MADD. Molecular analysis of gene revealed two novel heterozygous variants, a frameshift mutation c.1812delG (p.V605Yfs34) in exon 13 and a synonymous variant c.579A>G (p.E193E) in exon 5. The transcript analysis exhibited that the synonymous variant c.579A>G caused exon 5 skipping. The minigene splice assay confirmed the alteration of mRNA splicing which could lead to the production of a truncated protein. Supplementation of riboflavin, carnitine and low-fat diet improved the clinical symptoms. We firstly report a rare case of MADD with a pathogenic synonymous variant in the gene which highlights the importance and necessity of bioinformatic analysis and functional testing for synonymous variants when searching for causative gene mutations. The results expand the spectrum of pathogenic variants in MADD.
多种酰基辅酶A脱氢酶缺乏症（MADD）是一种常染色体隐性疾病，其特征为广泛的临床症状，包括肌肉无力、低血糖、代谢性酸中毒和多系统功能障碍。电子传递黄素蛋白脱氢酶（ETFDH）基因的功能丧失突变与MADD相关。迄今为止，尚未报道该基因中的致病同义变体。我们报告了一名中国女孩的临床病程，该女孩通过全外显子组测序被诊断为迟发性MADD。通过转录本分析和小基因剪接试验分析了变体对mRNA剪接的影响。这名6个月大的女孩最初表现出肌肉无力、肌张力减退、轻度肌源性损伤和脂肪肝。串联质谱法进行的血液和尿液代谢筛查提示为MADD。对该基因的分子分析揭示了两个新的杂合变体，一个是外显子13中的移码突变c.1812delG（p.V605Yfs34），另一个是外显子5中的同义变体c.579A>G（p.E193E）。转录本分析显示同义变体c.579A>G导致外显子5跳跃。小基因剪接试验证实了mRNA剪接的改变，这可能导致截短蛋白的产生。补充核黄素、肉碱和低脂饮食改善了临床症状。我们首次报告了一例罕见的MADD病例，该基因中存在致病同义变体，这突出了在寻找致病基因突变时对同义变体进行生物信息学分析和功能测试的重要性和必要性。研究结果扩展了MADD致病变体的谱。
