Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Department of Henan Newborn Screening Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Clin Chim Acta. 2022 Nov 1;536:155-161. doi: 10.1016/j.cca.2022.09.008. Epub 2022 Sep 9.
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.
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.
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.
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.
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.
中链酰基辅酶 A 脱氢酶缺乏症 (MCADD) 是一种罕见的脂肪酸 β-氧化遗传性代谢紊乱疾病，也是最常见的先天性代谢错误之一。MCADD 的发病率在不同地区和种族之间有所不同。迄今为止，中国仅报道了少数 MCADD 病例。
本研究旨在发现中国患者中新的遗传致病性变异，并评估中国不同地区高频 ACADM 致病性变异疾病的检出率。
通过串联质谱（MS/MS）在 245054 例新生儿中筛选出 6 例 MCADD 病例。对 6 例 MCADD 患儿的家系进行下一代测序。采用 REVEL 方法预测检测到的错义变异的蛋白质功能，采用 SPDBV 4.10 预测蛋白质 3D 结构模型。我们在 6 例 MCADD 患者中鉴定出 ACADM 基因的致病性变异，然后通过 Sanger 测序和关联分析对这些变异进行评估。
河南省新生儿 MCADD 的发病率为 1/40842。在这 6 例患者中，5 例为复合杂合变异，1 例为纯合变异。DNA 测序显示，ACADM 基因中存在 4 个已知突变（c.449_452del、c.1085G>A、c.1229T>C、c.589A>G）和 3 个新突变（c.849+5_849+8del、c.427A>G、c.1181C>T）。c.1085G>A（p.G362E）突变在河南人群中最为常见，且在中国北方和南方之间存在明显差异。
MCADD 在我国较为罕见，c.1085G>A（p.G362E）是河南人群中的常见突变。我们的研究结果，尤其是新的变异，将有助于提高对遗传背景的认识，并有助于为受影响的家庭提供临床诊断和遗传咨询。
