Abstract：
BACKGROUND: Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a rare inherited metabolic disorder of fatty acid β-oxidation and one of the most common inborn errors of metabolism. The incidence of MCADD varies among regions and ethnic groups. To date, few cases of MCADD have been documented in China.
OBJECTIVE: The present study aimed to find out the novel genetic pathogenic variants in the Chinese patients and evaluate the detection rate of the disease of high-frequency ACADM pathogenic variants in different regions of China.
METHODS: 6 cases of MCADD were screened by tandem mass spectrometric (MS/MS) among 245 054 newborns. We performed next-generation sequencing on 6 families of infants with MCADD. We used the REVEL method to predict the protein function of the detected missense variants and used SPDBV 4.10 to predict the protein 3D structure model. We identified pathogenic variants of ACADM gene in 6 cases of MCADD, and then assessed these variants through Sanger sequencing and association analysis.
RESULTS: The incidence of neonatal MCADD was 1/40,842 in Henan province. Among the 6 patients, five cases were compound heterozygous variants, one case was homozygous variants. DNA sequencing revealed 4 known (c.449_452del, c.1085G > A, c.1229 T > C, c.589A > G) and 3 novel mutations (c.849 + 5_849 + 8del, c.427A > G, c.1181C > T) in the ACADM gene. Mutation c.1085G > A (p.G362E) was most frequent among Henan people and shows obvious differences between North and South of China.
CONCLUSIONS: MCADD is relatively rare in China, and c.1085G > A (p.G362E) is a common mutation in Henan population. Our findings, especially novel variants, will help improve the understanding of the genetic background and have facilitated clinical diagnosis and genetic counseling for the affected families.
OBJECTIVE: The present study aimed to find out the novel genetic pathogenic variants in the Chinese patients and evaluate the detection rate of the disease of high-frequency ACADM pathogenic variants in different regions of China.
METHODS: 6 cases of MCADD were screened by tandem mass spectrometric (MS/MS) among 245 054 newborns. We performed next-generation sequencing on 6 families of infants with MCADD. We used the REVEL method to predict the protein function of the detected missense variants and used SPDBV 4.10 to predict the protein 3D structure model. We identified pathogenic variants of ACADM gene in 6 cases of MCADD, and then assessed these variants through Sanger sequencing and association analysis.
RESULTS: The incidence of neonatal MCADD was 1/40,842 in Henan province. Among the 6 patients, five cases were compound heterozygous variants, one case was homozygous variants. DNA sequencing revealed 4 known (c.449_452del, c.1085G > A, c.1229 T > C, c.589A > G) and 3 novel mutations (c.849 + 5_849 + 8del, c.427A > G, c.1181C > T) in the ACADM gene. Mutation c.1085G > A (p.G362E) was most frequent among Henan people and shows obvious differences between North and South of China.
CONCLUSIONS: MCADD is relatively rare in China, and c.1085G > A (p.G362E) is a common mutation in Henan population. Our findings, especially novel variants, will help improve the understanding of the genetic background and have facilitated clinical diagnosis and genetic counseling for the affected families.
摘要：
背景：中链酰基辅酶A脱氢酶缺乏症（MCADD）是一种罕见的遗传性脂肪酸β-氧化代谢紊乱，是最常见的先天性代谢错误之一。MCADD的发病率因地区和种族而异。迄今为止,在中国很少有MCADD病例被记录。
目的：本研究旨在找出中国患者的新的致病基因变异，并评估中国不同地区的ACADM高频致病基因变异的检出率。
方法：对245054例新生儿进行串联质谱(MS/MS)筛查6例MCADD。我们对6个MCADD婴儿家庭进行了下一代测序。我们使用REVEL方法预测检测到的错义变体的蛋白质功能，并使用SPDBV4.10预测蛋白质3D结构模型。我们在6例MCADD中确定了ACADM基因的致病变异，然后通过Sanger测序和关联分析评估这些变异。
结果：河南省新生儿MCADD发生率为1/40,842。在6名患者中，5例为复合杂合变异体,一例是纯合变异。DNA测序显示4个已知(c.449_452del，c.1085G>A，c.1229T>C，c.589A>G）和3个新突变（c.8495_8498del，c.427A>G，c.1181C>T）在ACADM基因中。突变c.1085G>A（p。G362E）在河南人中最常见，在中国南北之间表现出明显的差异。
结论：MCADD在中国相对罕见，和c.1085G>A（p。G362E)是河南人群中常见的突变。我们的发现,尤其是新颖的变体，将有助于提高对遗传背景的了解，并为受影响的家庭提供临床诊断和遗传咨询。
目的：本研究旨在找出中国患者的新的致病基因变异，并评估中国不同地区的ACADM高频致病基因变异的检出率。
方法：对245054例新生儿进行串联质谱(MS/MS)筛查6例MCADD。我们对6个MCADD婴儿家庭进行了下一代测序。我们使用REVEL方法预测检测到的错义变体的蛋白质功能，并使用SPDBV4.10预测蛋白质3D结构模型。我们在6例MCADD中确定了ACADM基因的致病变异，然后通过Sanger测序和关联分析评估这些变异。
结果：河南省新生儿MCADD发生率为1/40,842。在6名患者中，5例为复合杂合变异体,一例是纯合变异。DNA测序显示4个已知(c.449_452del，c.1085G>A，c.1229T>C，c.589A>G）和3个新突变（c.8495_8498del，c.427A>G，c.1181C>T）在ACADM基因中。突变c.1085G>A（p。G362E）在河南人中最常见，在中国南北之间表现出明显的差异。
结论：MCADD在中国相对罕见，和c.1085G>A（p。G362E)是河南人群中常见的突变。我们的发现,尤其是新颖的变体，将有助于提高对遗传背景的了解，并为受影响的家庭提供临床诊断和遗传咨询。
