摘要目的:探讨1例经新生儿疾病筛查拟诊为β-酮硫解酶缺乏症(β-ketothiolase deficiency，BKD)患儿的致病基因变异特点，明确其致病原因。方法:通过多重探针杂交富集患儿 ACAT1基因的全部编码区及其侧翼区序列进行高通量测序，确定可疑变异后应用Sanger测序进行变异位点验证。采用多种在线软件对所检出的变异进行致病性分析。 结果:在患儿 ACAT1基因检测到c.121-3C>G和c.275G>A(p.Gly92Asp)复合杂合变异。Sanger测序验证显示父亲和两个姐姐均携带c.121-3C>G杂合变异；家系其他成员均未检测到c.275G>A变异，但在该变异下游的第4内含子检出患儿携带c.334＋172C>G(rs12226047)杂合多态性改变，其两个姐姐及母亲也检测到相同SNP位点，其父亲未检测到此SNP位点。表明c.275G>A与172C位于同一染色体上。经软件预测，提示c.121-3C>G和c.275G>A变异均为有害性。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， ACAT1基因c.275G>A变异为致病性变异(PS2＋PM2＋PM3＋PP3＋PP4)；c.121-3C>G变异为可能致病性变异(PM2＋PM3＋PP3＋PP4)。 结论:ACTAT1基因c.121-3C>G和c.275G>A变异可能是患儿的致病原因，本研究变异类型丰富了 ACAT1基因的变异谱。

abstractsObjective:To explore the genetic etiology of a child suspected for β-ketothiolase deficiency by neonatal screening.Methods:All coding exons and flanking sequences of the ACAT1 gene were subjected to targeted capture and high-throughput sequencing. Suspected variants were verified by Sanger sequencing and bioinformatic analysis. Results:The child was found to harbor compound heterozygous variants of the ACAT1 gene, namely c. 121-3C>G and c. 275G>A (p.Gly92Asp). The c. 121-3C>G variant was also detected in his father and two sisters, while the c. 275G>A (p.Gly92Asp) was a de novo variant. A c. 334+ 172C>G (rs12226047) polymorphism was also detected in his mother and two sisters. Sanger sequencing has verified that the c. 275G>A (p.Gly92Asp) and c. 334+ 172C>G (rs12226047) variants are located on the same chromosome. Bioinformatics analysis suggested both c. 121-3C>G and c. 275G>A (p.G92D) variants to be damaging. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c. 275G>A variant of ACAT1 gene was predicted to be pathogenic(PS2+ PM2+ PM3+ PP3+ PP4), the c. 121-3C>G variant to be lilkly pathogenic(PM2+ PM3+ PP3+ PP4). Conclusion:The c. 121-3C>G and c. 275G>A variants of ACAT1 gene probably underlay the pathogenesis of the child. Above finding has enriched the variant spectrum of the ACAT1 gene.