ACAD8基因新突变导致异丁酰辅酶A脱氢酶缺乏症的遗传学分析

Genetic analysis of a Chinese family with isobutyryl-CoA dehydrogenase deficiency caused by two novel mutations in the ACAD8 gene

目的对一个新生儿代谢筛查异常患儿进行遗传学病因分析和遗传咨询。方法采集患儿及父母外周血,经DNA提取后进行先证者单人全外显子组测序,根据ACMG指南筛选出致病性位点并通过Sanger测序验证父母来源。结果全外结果发现患儿携带ACAD8基因c.302C>T(p.S101L)和c.712del(p.W238Gfs*9),均为杂合变异,父母分别为杂合变异携带者。根据美国医学遗传学与基因组学学会遗传变异分类标准与指南进行变异致病性评级,这两个变异均为疑似致病性变异,其致病性均为首次报道。基因ACAD8突变会导致常染色体隐性遗传疾病异丁酰辅酶A脱氢酶缺乏症(IBDD)。该患儿无特异性临床表现,随访至20月龄生长发育正常,亦未见异常。结论我们在IBDD患者中发现了ACAD8基因两个新突变c.302C>T(p.S101L)和c.712del(p.W238Gfs*9),丰富了人类ACAD8基因的致病性突变谱,从而有助于了解IBDD患者的遗传背景。同时为了进一步描述该遗传代谢病的临床表型,长期随访和监测是十分必要的。

Objective To conduct genetic analysis and genetic counseling for a child with abnormal newborn metabolic screening.Methods The peripheral blood of the children and their parents was collected.After DNA extraction,whole exome sequencing of the proband was performed.The pathogenic sites were screened out according to ACMG guidelines and the source of the parents was verified by Sanger sequencing.Results WES results showed that the child carried c.302C>T(p.S101L)and c.712del(p.W238Gfs*9)mutation of ACAD8 gene,both of which were heterozygous variants,and their parents were carriers of heterozygous variants respectively.According to ACMG guidelines,these two variants are suspected pathogenic variants,and their pathogenicity has not been reported in the literature.Mutations in the gene ACAD8 may lead to an autosomal recessive inherited disease called isobutyryl-CoA dehydrogenase deficiency(IBDD).The child had no specific clinical manifestations,and was followed up to 20 months of age with normal growth and development.Conclusion We discovered two new mutations in the ACAD8 gene c.302C>T(p.S101L)and c.712del(p.W238Gfs*9)in patients with IBDD,which enriched the pathogenic mutation spectrum of the human ACAD8 gene,and thus it helps to understand the genetic background of IBDD patients.While in order to further describe the clinical phenotype of this genetic metabolic disease,long-term follow-up and monitoring are very necessary.