疑似遗传代谢病的高危新生儿行质谱检测与高通量测序检测诊断准确性研究
|
摘要
目的比较质谱检测与高通量测序(NGS)筛查疑似遗传代谢病(IMD)的高危新生儿的诊断效能。方法纳入2016年8月至2018年6月复旦大学附属儿科医院(我院)临床表现疑似IMD的高危新生儿,患儿监护人知情同意患儿参加质谱检测和NGS筛查IMD,以NGS检测(包含2 742个已知致病基因)为金标准,以质谱检测(包含20种氨基酸代谢病、12种脂肪酸代谢病和19种有机酸代谢病)为待测标准,随访至6月龄结局。结果纳入2 000例疑似IMD的高危新生儿,NGS诊断IMD 33例(1.7%),涉及21种IMD;质谱检测结果异常154例(7.7%),提示IMD可能26例、继发性改变可能128例。以NGS检测结果为金标准,质谱检测提示IMD可能+提示继发性改变可能为待测标准1,质谱检测的敏感度93.9%(95%CI:79.8%～99.3%),特异度93.8%(95%CI:92.6%～94.8%)。质谱检测提示IMD可能(待测标准2)与NGS相符13例;质谱检测提示某一类或某几种IMD可能11例,NGS均明确并细化了疾病类型;质谱检测提示IMD可能,但与NGS检测结果不一致2例;质谱检测提示继发性改变可能5例,NGS检测为致病/可疑致病变异,明确并细化了疾病类型。待测标准1中,质谱结果正常的1 846例中,NGS发现2例IMD。NGS诊断的IMD有5例不包含在本文质谱检测的病种中。NGS诊断IMD 33例,有机酸代谢异常8种15例、氨基酸代谢异常7种9例、脂肪酸氧化代谢异常3种6例、其他类型IMD共3例;可疑遗传代谢病家庭史12例;以6月龄为随访终点统计,13例IMD患儿家属放弃治疗死亡,2例抢救无效死亡; 18例IMD患儿临床诊疗方案得以明确,7例因获得及时有效的治疗目前生长发育良好,11例有不同程度的发育落后,主要以精神运动发育迟缓为主,部分伴有听力损害。结论质谱检测+NGS检测较单纯质谱检测可以更加快速且全面确诊临床表现疑似IMD的高危新生儿,尽早实施个体化治疗,改善患儿预后。
Objective To compare the diagnostic accuracy of mass spectrometry and high throughput sequencing in screening neonates at high risk of suspected inherited metabolic disorders( IMD). Methods Neonates with suspected IMD were referred to mass spectrometry and next generation sequencing( NGS) with the consent of their guardians from August 2016 to June 2018.Taking NGS( containing 2 742 known pathogenic genes) as the gold standard,the diagnostic value of mass spectrometry( screening diseases including 20 amino acid metabolic diseases,12 fatty acid metabolic diseases and 19 organic acid diseases) for IMD was discussed. Results Thirty-three of 2 000 neonates with suspected IMD were diagnosed by NGS,including 8 kinds of abnormal organic acid metabolism( 15 cases),7 kinds of abnormal amino acid metabolism( 9 cases),3 kinds of abnormal fatty acid oxidation metabolism( 6 cases) and 3 cases of other types of IMD. In these patients,mass spectrometry indicated that there were 128 cases of secondary changes and 26 cases of IMD. When both IMD and secondary changes were considered positive according to the results of mass spectrometry,the sensitivity and specificity of mass spectrometry were 93.9%( 95%CI: 79.8%-99.3%) and 93.8%( 95%CI:92.6%-94.8%) respectively. In special types of IMD indicated by mass spectrometry,there were 13 cases consistent with NGS,but2 cases were inconsistent with NGS. Indicated by mass spectrometry,NGS detected pathogenic/likely pathogenic variants of related IMD in 11 cases with several alternatives of IMD,5 cases with secondary changes and 2 cases with normal results. Five IMDs identified by NGS were not included in the disease spectrum of mass spectrometry in our study. Among the patients with IMD,12 had family history of suspected IMD. In the 6 thmonth after birth,13 cases with IMD died of abandoned treatments and 2 cases died of invalid rescue. NGS established therapeutic schemes for 18 infants with IMD. In these patients,7 developed well and 11 had developmental delay,mainly psychomotor retardation,some of which had hearing impairment. Conclusion Compared with mass spectrometry,the combination of mass spectrometry and NGS can diagnose neonates of suspected IMD more quickly so as to implement individualized treatment as early as possible and improve the prognosis of patients.
Objective To compare the diagnostic accuracy of mass spectrometry and high throughput sequencing in screening neonates at high risk of suspected inherited metabolic disorders( IMD). Methods Neonates with suspected IMD were referred to mass spectrometry and next generation sequencing( NGS) with the consent of their guardians from August 2016 to June 2018.Taking NGS( containing 2 742 known pathogenic genes) as the gold standard,the diagnostic value of mass spectrometry( screening diseases including 20 amino acid metabolic diseases,12 fatty acid metabolic diseases and 19 organic acid diseases) for IMD was discussed. Results Thirty-three of 2 000 neonates with suspected IMD were diagnosed by NGS,including 8 kinds of abnormal organic acid metabolism( 15 cases),7 kinds of abnormal amino acid metabolism( 9 cases),3 kinds of abnormal fatty acid oxidation metabolism( 6 cases) and 3 cases of other types of IMD. In these patients,mass spectrometry indicated that there were 128 cases of secondary changes and 26 cases of IMD. When both IMD and secondary changes were considered positive according to the results of mass spectrometry,the sensitivity and specificity of mass spectrometry were 93.9%( 95%CI: 79.8%-99.3%) and 93.8%( 95%CI:92.6%-94.8%) respectively. In special types of IMD indicated by mass spectrometry,there were 13 cases consistent with NGS,but2 cases were inconsistent with NGS. Indicated by mass spectrometry,NGS detected pathogenic/likely pathogenic variants of related IMD in 11 cases with several alternatives of IMD,5 cases with secondary changes and 2 cases with normal results. Five IMDs identified by NGS were not included in the disease spectrum of mass spectrometry in our study. Among the patients with IMD,12 had family history of suspected IMD. In the 6 thmonth after birth,13 cases with IMD died of abandoned treatments and 2 cases died of invalid rescue. NGS established therapeutic schemes for 18 infants with IMD. In these patients,7 developed well and 11 had developmental delay,mainly psychomotor retardation,some of which had hearing impairment. Conclusion Compared with mass spectrometry,the combination of mass spectrometry and NGS can diagnose neonates of suspected IMD more quickly so as to implement individualized treatment as early as possible and improve the prognosis of patients.
引文
[1]Meng M,Zhang YP. Impact of inborn errors of metabolism on admission in a neonatal intensive care unit:a 4-year report. J Pediatr Endocrinol Metab,2013,26(7-8):689-693
[2]Ozben T. Expanded newborn screening and confirmatory followup testing for inborn errors of metabolism detected by tandem mass spectrometry. Clin Chem Lab Med,2013,51(1):157-176
[3]Park KJ,Park S,Lee E,et al. A population-based genomic study of inherited metabolic diseases detected through newborn screening. Ann Lab Med,2016,36(6):561-572
[4]黎籽秀,刘博,徐凌丽,等.高通量测序数据分析和临床诊断流程的解读.中国循证儿科杂志,2015,10(1):19-24
[5]杨琳,董欣然,彭小敏.复旦大学附属儿科医院高通量测序数据分析流程(第二版)对遗传疾病候选变异基因筛选用时和准确性分析.中国循证儿科杂志,2018,2(13):118-123
[6]Willig LK,Petrikin JE,Smith LD,et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants:a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med,2015,3(5):377-387
[7]Meng L,Pammi M,Saronwala A,et al. Use of exome sequencing for infants in Intensive Care Units:Ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr,2017,171(12):e173438
[8]Lehotay DC,Hall P,Lepage J,et al. LC-MS/MS progress in newborn screening. Clin Biochem,2011,44(1):21-31
[9]叶圆圆,王薇,何法霖,等.我国新生儿遗传代谢病串联质谱筛查室内质控变异系数分析.临床检验杂志,2016,34(12):901-903
[10]Sass JO,Gemperle-Britschgi C,Tarailo-Graovac M,et al.Unravelling 5-oxoprolinuria(pyroglutamic aciduria)due to biallelic OPLAH mutations:20 new mutations in 14 families.Mol Genet Metab,2016,119(1-2):44-49
[11]Hayasaka K,Numakura C,Watanabe H.Treatment and pathomechanism of citrin deficiency. Brain Nerve,2015,67(6):739-747
[12]Wortmann SB,Duran M,Anikster Y,et al. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature:proper classification and nomenclature. J Inherit Metab Dis,2013,36(6):923-928
[2]Ozben T. Expanded newborn screening and confirmatory followup testing for inborn errors of metabolism detected by tandem mass spectrometry. Clin Chem Lab Med,2013,51(1):157-176
[3]Park KJ,Park S,Lee E,et al. A population-based genomic study of inherited metabolic diseases detected through newborn screening. Ann Lab Med,2016,36(6):561-572
[4]黎籽秀,刘博,徐凌丽,等.高通量测序数据分析和临床诊断流程的解读.中国循证儿科杂志,2015,10(1):19-24
[5]杨琳,董欣然,彭小敏.复旦大学附属儿科医院高通量测序数据分析流程(第二版)对遗传疾病候选变异基因筛选用时和准确性分析.中国循证儿科杂志,2018,2(13):118-123
[6]Willig LK,Petrikin JE,Smith LD,et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants:a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med,2015,3(5):377-387
[7]Meng L,Pammi M,Saronwala A,et al. Use of exome sequencing for infants in Intensive Care Units:Ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr,2017,171(12):e173438
[8]Lehotay DC,Hall P,Lepage J,et al. LC-MS/MS progress in newborn screening. Clin Biochem,2011,44(1):21-31
[9]叶圆圆,王薇,何法霖,等.我国新生儿遗传代谢病串联质谱筛查室内质控变异系数分析.临床检验杂志,2016,34(12):901-903
[10]Sass JO,Gemperle-Britschgi C,Tarailo-Graovac M,et al.Unravelling 5-oxoprolinuria(pyroglutamic aciduria)due to biallelic OPLAH mutations:20 new mutations in 14 families.Mol Genet Metab,2016,119(1-2):44-49
[11]Hayasaka K,Numakura C,Watanabe H.Treatment and pathomechanism of citrin deficiency. Brain Nerve,2015,67(6):739-747
[12]Wortmann SB,Duran M,Anikster Y,et al. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature:proper classification and nomenclature. J Inherit Metab Dis,2013,36(6):923-928