黔西北地区新生儿遗传代谢病筛查及基因变异谱分析

Newborn screening for inherited metabolic diseases and genetic variant spectrum analysis in northwestern Guizhou,China

摘要

目的 探讨黔西北地区新生儿遗传代谢病(IMD)筛查的实施效果及基因突变谱特征,了解该地区遗传代谢病发病特点,为新生儿出生缺陷的早期诊断与干预提供依据。方法 回顾性分析2023年9月—2024年9月黔西北毕节市下辖的8个县(区)46 078例新生儿的筛查资料,采用串联质谱技术检测干血片氨基酸、酰基肉碱等代谢物,定量分析33种IMD,检测结果阳性新生儿,经基因诊断予以确定或排除。统计筛查阳性率、患病率,分析致病突变分布特征。结果 46 078例新生儿中,270例筛查阳性,筛查阳性率0.59%;249例完成基因诊断,确诊26例,总体检出率为0.56‰,其中高苯丙氨酸血症7例,短链酰基辅酶A脱氢酶缺乏症7例,2-甲基丁酰辅酶A脱氢酶缺乏症6例,高甲硫氨酸血症5例,希特林蛋白缺乏症1例。26例患儿共检出6个基因22种变异,本研究报道新变异1例(MAT1A c.680dup:p.Arg228GlnfsTer38),发现潜在热点ACADS变异2例。结论 黔西北地区遗传代谢病总体检出率较高,以高苯丙氨酸血症、短链酰基辅酶A脱氢酶缺乏症、2-甲基丁酰辅酶A脱氢酶缺乏症为主,存在民族聚集现象。建议将上述高发疾病纳入本地筛查重点,加强民族聚集区的基因诊断与遗传咨询,持续监测新发及热点变异,优化出生缺陷防控策略。

Abstract

Objective To investigate the implementation effect of newborn screening for inherited metabolic diseases (IMDs) in Northwestern Guizhou, and to characterize the genetic mutation spectrum, so as to understand the regional epidemiological features and provide evidence for early diagnosis and intervention of birth defects. Methods This retrospective study included 46 078 newborns screened in eight counties or districts of Bijie in northwestern Guizhou between September 2023 and September 2024.Dried blood spot amino acids and acylcarnitines were analyzed by tandem mass spectrometry to screen for 33 IMDs.Screen-positive newborns were recalled for repeat testing and genetic diagnosis.The screen-positive rate, genetically confirmed case detection rate, and pathogenic variant distribution were analyzed. Results Among 46 078 neonates screened by MS/MS, 270 cases were positive, yielding a positive rate of 0.59%.Genetic testing was completed in 249 newborns, and 26 were confirmed to have IMDs, yielding an overall detection rate of 0.56‰.The confirmed disorders comprised hyperphenylalaninemia (n=7), short-chain acyl-CoA dehydrogenase deficiency (n=7), 2-methylbutyryl-CoA dehydrogenase deficiency (n=6), hypermethioninemia (n=5), and citrin deficiency (n=1).Twenty-two variants in six genes were identified, including a novel MAT1A frameshift variant[c.680dup (p.Arg228GlnfsTer38)]and two candidate recurrent ACADS variants. Conclusions The detection rate of IMD in northwestern Guizhou is relatively high.Hyperphenylalaninemia, short-chain acyl-CoA dehydrogenase deficiency, and 2-methylbutyryl-CoA dehydrogenase deficiency are the most frequently identified disorders, and evidence of ethnic clustering is observed.These disorders should be prioritized in local newborn screening programs.Genetic diagnosis and counseling should be strengthened in areas with ethnically clustered populations, while surveillance of newly identified and recurrent variants should be continued to optimize birth-defect prevention and control strategies.

关键词

新生儿疾病筛查 / 遗传代谢病 / 出生缺陷 / 串联质谱 / 基因诊断

Key words

newborn screening / inherited metabolic diseases / birth defects / tandem mass spectrometry / gene diagnosis

[1] Ijaz A, Abbas S, Shabbir M, et al.Inherited metabolic disorders:Presentation, clinical types, laboratory diagnosis and genetic markers[J].Orphanet J Rare Dis, 2025, 20(1): 422.
[2] 中华预防医学会出生缺陷预防与控制专业委员会新生儿遗传代谢病筛查学组.新生儿筛查遗传代谢病诊治规范专家共识[J].中华新生儿科杂志, 2023, 38(7): 385-394.
The Group of Newborn Screening, Society of Birth Defects Prevention and Control, Chinese Preventive Medicine Association.Consensus on diagnosis and treatment of inherited metabolic diseases by newborn screening[J].Chin J Neonatol, 2023, 38(7): 385-394.(in Chinese)
[3] 张会婷, 杨艳玲.新生儿筛查是防控出生缺陷的防火墙[J].中华全科医师杂志, 2023, 22(5): 456-462.
Zhang HT, Yang YL.Newborn screening is crucial for prevention and control of birth defects[J].Chin J Gen Pract, 2023, 22(5): 456-462.(in Chinese)
[4] 丁洁, 张婷, 韩新儒, 等.2015—2022年嘉兴市基于串联质谱技术新生儿遗传代谢病筛查及确诊患儿基因变异谱分析[J].中国儿童保健杂志, 2025, 33(6): 664-670.
Ding J, Zhang T, Han XR, et al.Screening results of inborn errors of metabolism based on tandem mass spectrometry and gene variation spectrum analysis of confirmed children in Jiaxing City from 2015 to 2022[J].Chin J Child Health Care, 2025, 33(6): 664-670.(in Chinese)
[5] 胡勤, 何艺, 韦懿.新生儿遗传代谢病串联质谱筛查影响因素和基因检测结果分析[J].中国妇幼保健, 2022, 37(10): 1891-1895.
[6] Tan J, Chen D, Chang R, et al.Tandem mass spectrometry screening for inborn errors of metabolism in newborns and high-risk infants insouthern China: Disease spectrum and genetic characteristics in a Chinese population[J].Front Genet, 2021, 12: 631688.
[7] 杨茹莱, 舒强.新生儿遗传代谢病筛查阳性及确诊患者的管理[J].中国实用儿科杂志, 2023, 38(7): 513-516.
Yang RL, Shu Q.Management of positive screening and confirmed patients with neonatal genetic metabolic diseases[J].Chin J Pract Pediatr, 2023, 38(7): 513-516.(in Chinese)
[8] 中华人民共和国国家卫生健康委员会.《新生儿疾病筛查技术规范(2010年版)》[EB/OL].(2010-11-10)[2026-01-02].https://www.nhc.gov.cn/wjw/c100175/201012/f9005a3ba
04140898b4c333aebad0a46.shtml
[9] 国家卫健委临床检验中心新生儿疾病筛查室间质量评价委员会.新生儿疾病筛查滤纸血片采集和递送及保存专家共识[J].中华检验医学杂志, 2019, 42(10): 836-840.
[10] 卫生部临床检验中心新生儿遗传代谢疾病筛查室间质量评价委员会,北京医院国家老年医学中心卫生部临床检验中心/北京市临床检验工程技术研究中心.新生儿疾病串联质谱筛查技术专家共识[J].中华检验医学杂志, 2019, 42(2): 89-97.
[11] 王维鹏, 邹琳, 王治国.新生儿疾病筛查与产前诊断实验室管理[M].北京: 人民卫生出版社, 2018.
[12] den Dunnen JT, Dalgleish R, Maglott DR, et al.HGVS recommendations for the description of sequence variants: 2016 update[J].Hum Mutant, 2016, 37(6): 564-569.
[13] 中华预防医学会出生缺陷预防与控制专业委员会新生儿筛查学组,中华医学会儿科学分会临床营养学组,中国医师协会医学遗传医师分会临床生化遗传专业委员会,等.苯丙氨酸羟化酶缺乏症饮食治疗与营养管理共识[J].中华儿科杂志,2019,57(6): 405-409.
The Group of Newborn Screening, Society of Birth Defects Prevention and Control, Chinese Preventive Medicine Association; the Group of Clinical Nutrition, Society of Pediatrics, Chinese Medical Association; the Committee of Clinical Biochemistry and Genetics, Society of Medical Genetics, Chinese Medical Doctor Association, et al.Consensus statement on dietary treatment and nutritional management for phenylalanine hydroxylase deficiency[J].Chin J Pediatr, 2019, 57(6):405-409.(in Chinese)
[14] 张瑞雪, 宋成荣, 张言, 等.串联质谱联合二代测序技术在陕西地区遗传代谢病诊断中的应用[J].国际遗传学杂志, 2020, 43(6): 317-323.
Zhang RX, Song CR, Zhang Y, et al.Application of tandem mass spectrometry combined with next generation sequencing in the diagnosis of inborn errors of metabolism in Shanxi Province[J].Int J Genet, 2020, 43(6): 317-323.(in Chinese)
[15] 李育霖, 孙萌, 李盼盼, 等.新生儿甲基丙二酸血症生化筛查与基因筛查结果分析[J].中华实用儿科临床杂志, 2023, 38(1): 54-59.
Li YL, Sun M, Li PP, et al.Analysis of biochemical and genetic screening results for neonatal methylmalonic acidemia[J].Chin J Appl Clin Pediatr, 2023, 38(1): 54-59.(in Chinese)
[16] 唐诚芳, 谭敏沂, 谢婷, 等.广州地区新生儿遗传代谢病串联质谱法筛查结果及筛查性能评估[J].浙江大学学报(医学版), 2021, 50(4): 463-471.
Tang CF, Tan MY, Xie T, et al.Screening for neonatal inherited metabolic disorders by tandem mass spectrometry in Guangzhou[J].J Zhejiang Univ (Med Sci), 2021, 50(4): 463-471.(in Chinese)
[17] 顾学范, 韩连书, 余永国.中国新生儿遗传代谢病筛查现状及展望[J].罕见病研究, 2022, 1(1): 13-19.
Gu XF, Han LS, Yu YG.Current status and prospects of screening for newborn hereditary metabolic disease[J].J Rare Dis, 2022, 1(1): 13-19.(in Chinese)
[18] Xiao G, Feng Z, Xu C, et al.206 977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in Huaihua, China[J].Front Genet, 2024, 15: 1387423.
[19] Hübner V, Hannibal L, Janzen N, et al.Methionine adenosyltransferase Ⅰ/Ⅲ deficiency detected by newborn screening[J].Genes, 2022, 13(7): 1163.
[20] Tong F, Zhang Y, Chen C, et al.Long-term prognosis of 35 patients with methionine adenosyltransferase deficiency based on newborn screening in China[J].Front Cell Dev Biol, 2023, 10: 1059680.
[21] Lin Y, Lin C, Zheng Z, et al.Large-scale newborn screening for organic acidemias in Quanzhou, China: A 10-year retrospective observational study[J].Sci Rep, 2025, 15: 30592.
[22] Wolfe L, Jethva R, Oglesbee D, et al.Short-chain acyl-CoA dehydrogenase deficiency[M].Adam MP, Bick S, Mirzaa GM, et al.GeneReviews^®.Seattle (WA): University of Washington, 1993-2026.https://www.ncbi.nlm.nih.gov/books/NBK63582/.
[23] Lin Y, Gao H, Lin C, et al.Biochemical, clinical, and genetic characteristics of short/branched chain acyl-CoA dehydrogenase deficiency in Chinese patients by newborn screening[J].Front Genet, 2019, 10: 802.
[24] Adhikari AN, Currier RJ, Tang H, et al.Genomic analysis of historical cases with positive newborn screens for short-chain acyl-CoA dehydrogenase deficiency shows that a validated second-tier biochemical test can replace future sequencing[J].Int J Neonatal Screen, 2020, 6(2): 41.
[25] Breilyn MS, Kenny EE, Abul-Husn NS.Diverse and unselected adults with clinically relevant ACADS variants lack evidence of metabolic disease[J].Mol Genet Metab, 2023, 138(1): 106971.
[26] 陈敏, 尹一帆, 刘浩, 等.重庆市新生儿脂肪酸氧化代谢病筛查及确诊患儿随访分析[J].浙江大学学报(医学版), 2022, 51(3): 290-297.
Chen M, Yin YF, Liu H, et al.Screening for newborn fatty acid oxidation disorders in Chongqing and the follow-up of confirmed children[J].J Zhejiang Univ(Med Sci), 2022, 51(3): 290-297.(in Chinese)
[27] 王欣荣, 刘艳秋, 官慧珍, 等.126 111例新生儿串联质谱遗传代谢病筛查结果及基因突变情况分析[J].江西医药, 2022, 57(7): 707-710.

基金资助

重庆市科技局面上项目(cstc2021jcyj-msxmX0003);重庆市科卫联合面上项目(2025MSXM031);毕节市科学技术项目(毕科联合[2022]8号)