Exploratory Study on Screening of Multiple Inherited Metabolic Disorders in Newborns in Hainan Province

doi:10.12114/j.issn.1007-9572.2025.0292

Abstract

Abstract:

Background

The prevalence of neonatal inherited metabolic disorders exceeds 0.5%. This study represents the first comprehensive population-wide screening for these conditions in Hainan Province, contributing to the prevention and control of birth defects in the region and establishing diagnostic laboratory capabilities for inherited metabolic diseases.

Objective

To investigate the incidence of multiple inherited metabolic disorders (IMDs) among newborns in Hainan Province and provide reliable methods and data to support birth defect prevention and control.

Methods

This study used dried blood spot (DBS) samples collected from heel pricks of newborns born between February and December 2024 across all obstetric healthcare facilities in Hainan Province. Screening was performed using tandem mass spectrometry, and reference ranges for relevant biomarkers were established using the percentile method. Suspected cases were recalled for confirmatory diagnosis via gas chromatography-mass spectrometry (GC-MS) and gene sequencing.

Results

A total of 84 184 DBS samples from newborns were collected. Using the percentile method, reference ranges for 14 amino acids, 36 acylcarnitines, 1 ketone, 2 adenosines, and 4 lysophosphatidylcholines were established in 29 676 samples, providing the first normative reference data for Hainan Province. Thirty-eight cases of IMDs were diagnosed, yielding an incidence rate of 1/2 215 (38/84 184). Twelve distinct diseases were confirmed, including phenylketonuria (PKU), hypermethioninemia (HMet), multiple sulfatase deficiency (MUSD), citrin deficiency (CD), primary carnitine deficiency (PCD), short-chain acyl-CoA dehydrogenase deficiency (SCADD), carnitine palmitoyltransferaseⅠ deficiency (CPTⅠ), carnitine-acylcarnitine translocase deficiency (CACT), 3-methylcrotonyl-CoA carboxylase deficiency (MCCD), glutaric acidemia typeⅠ (GA-Ⅰ), glutaric acidemia typeⅡ (GA-Ⅱ), and short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD), with incidence rates ranging widely from 1/84 184 to 1/6 475. PCD (13 cases), SCADD (6 cases), and CD (5 cases) ranked as the three most prevalent disorders. 42 mutation sites across 12 genes were identified.

Conclusion

This study establishes the first reference ranges for newborn IMD screening in Hainan Province, providing critical reference criteria for subsequent screening programs. Following the implementation of a comprehensive free screening initiative, the data revealed a relatively high incidence of IMDs in Hainan newborns, with notable genetic complexity and diversity. Disorders of fatty acid metabolism-PCD, SCADD, and CD-were the most frequently detected. These findings underscore the importance of expanded newborn IMD screening in Hainan Province for the prevention and control of birth defects.

Key words: Neonatal screening, Inherited metabolic disorders, Dried blood spots, Incidence rate, Newborn screening, Hainan Province

摘要：

背景

我国新生儿遗传代谢病的患病率高于0.5%，本研究首次在海南省全域内进行新生儿遗传代谢病的筛查，有助于海南省的出生缺陷防控，为遗传代谢病的诊断提供实验室检测手段。

目的

探索海南省新生儿多种遗传代谢病发病情况，为海南省出生缺陷防控提供可靠的方法和参考依据。

方法

以2024年2—12月出生在海南省各助产医疗机构的新生儿足跟血干血斑为样本，筛查采用串联质谱法，并利用百分位定位法计算相关检测指标参考范围。疑似样本召回使用气相质谱法及测序法进行诊断验证。

结果

共收集84 184例新生儿足跟血干血斑样本。利用百分位定位法在29 676例样本中计算出了14种氨基酸、36种肉碱、1种酮、2种腺苷和4种溶血卵磷脂的海南省新生儿参考范围。诊断新生儿多种遗传代谢病38例，发病率为1/2 215（38/84 184）。确诊疾病12种：苯丙酮尿症（PKU）、高甲硫氨酸血症（HMet）、枫糖尿病（MUSD）、希特林蛋白缺乏症（CD）、原发性肉碱缺乏症（PCD）、短链酰基辅酶脱氢酶缺乏症（SCADD）、榈酰肉碱转移酶缺乏症Ⅰ型（CPTⅠ）、肉碱酰基转移酶缺乏症（CACT）、3-甲基巴豆酰辅酶A羧化酶缺乏症（MCCD）、戊二酸血症Ⅰ型（GA-Ⅰ）、戊二酸血症Ⅱ型（GA-Ⅱ）、2-甲基丁酰甘氨酸尿症（SBCADD），发病率1/84 184~1/6 475，差异较大。检出病种的前3位依次为PCD（13例）、SCADD（6例）和CD（5例）。检出12个基因共42个位点突变。

结论

首次确定了海南省新生儿多种遗传代谢病筛查的参考范围，为后续遗传代谢病筛查提供了判定指标，实施全面免费筛查后首次确定了海南省新生儿多种遗传代谢病发病率较高，且基因复杂多样，以脂肪酸代谢障碍的PCD、SCADD、CD较为多见。新生儿多种遗传代谢病筛查在海南出生缺陷防控方面具有重要意义。

关键词: 新生儿筛查, 遗传代谢病, 干血斑, 发病率, 新生儿疾病筛查, 海南省

CLC Number:

R 722

ZHAO Peizhen,ZHAO Zhendong,XU Haizhu. Exploratory Study on Screening of Multiple Inherited Metabolic Disorders in Newborns in Hainan Province[J]. Chinese General Practice, 2026, 29(30): 4438-4444. DOI: 10.12114/j.issn.1007-9572.2025.0292.
赵佩珍,赵振东,许海珠. 海南省新生儿多种遗传代谢病筛查的探索性研究[J]. 中国全科医学, 2026, 29(30): 4438-4444. DOI: 10.12114/j.issn.1007-9572.2025.0292.

Figures/Tables 3

References 27

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指标	百分位定位法						试剂盒参考范围	新参考范围
指标	P_0.1	P_0.5	P_1.0	P_99.0	P_99.5	P_99.9	试剂盒参考范围	新参考范围
ALA	115.60	139.17	150.46	497.83	529.09	612.49	136.41~541.37	140~600
ARG	0.98	1.14	1.24	30.54	37.42	55.09	1.33~34.41	1~38
ASA	0.02	0.04	0.05	0.99	1.14	1.56	0.01~1.09	0~1.1
CIT	4.19	4.91	5.31	23.78	27.08	36.93	5.85~28.99	4.9~27.0
GLN	101.29	136.59	161.23	905.12	958.07	1 117.58	129.46~950.47	100~1 100
GLU	86.54	109.44	123.90	678.48	732.20	859.08	114.14~469.10	90~850
GLY	125.91	152.19	169.58	707.30	766.98	894.84	191.89~870.58	126~900
LEU	54.91	66.20	71.76	249.04	265.07	310.31	69.03~222.81	55~265
MET	5.75	7.27	7.90	31.32	34.57	44.90	7.51~30.23	7.3~35.0
ORN	31.43	38.42	42.16	188.11	210.72	276.52	41.82~180.60	39~275
PHE	22.08	26.85	29.07	84.78	90.95	114.21	23.98~80.81	22~90
PRO	55.04	71.43	77.91	250.29	270.41	316.56	81.37~257.16	55~316
SA	0.00	0.00	0.00	0.60	0.74	0.99	0~0.71	0~0.74
TYR	23.18	29.71	32.86	186.88	214.38	294.53	30.54~232.96	23~294
VAL	48.04	57.11	61.35	208.92	227.05	276.60	65.59~211.08	48~230
ADO	0.24	0.30	0.34	3.54	4.07	5.03	0.15~2.89	0.15~3.50
D-ADO	0.00	0.00	0.00	0.07	0.08	0.10	0~0.06	0~0.08
C0	7.44	9.90	10.92	57.20	65.00	91.54	10.08~57.80	9.9~65.0
C2	2.62	4.94	5.85	35.67	39.51	49.23	6.39~44.50	4.94~40.00
C3	0.30	0.47	0.57	4.70	5.33	6.66	0.65~6.04	0.47~5.33
C3DC+C4OH	0.02	0.03	0.04	0.28	0.32	0.46	0.03~0.34	0.02~0.32
C4	0.05	0.07	0.08	0.38	0.43	0.63	0.07~0.45	0.07~0.43
C4DC+C5OH	0.08	0.10	0.11	0.56	0.65	0.89	0.10~0.61	0.10~0.65
C5	0.03	0.04	0.04	0.23	0.27	0.41	0.03~0.27	0.03~0.27
C5：1	0.00	0.00	0.00	0.02	0.02	0.03	0~0.02	0~0.03
C5DC+C6OH	0.02	0.02	0.02	0.14	0.16	0.21	0.02~0.14	0.02~0.21
C6	0.01	0.01	0.01	0.08	0.09	0.13	0.01~0.09	0.01~0.09
C6DC	0.01	0.02	0.02	0.11	0.13	0.16	0.01~0.12	0.02~0.16
C8	0.02	0.02	0.02	0.11	0.13	0.18	0.02~0.12	0.02~0.13
C8：1	0.01	0.02	0.02	0.18	0.21	0.29	0.02~0.22	0.01~0.21
C10	0.01	0.02	0.02	0.15	0.17	0.23	0.02~0.21	0.02~0.17
C10：1	0.01	0.02	0.02	0.09	0.10	0.13	0.01~0.11	0.02~0.10
C10：2	0.00	0.00	0.00	0.02	0.02	0.03	0~0.02	0~0.02
C12	0.01	0.01	0.01	0.17	0.20	0.26	0.02~0.22	0.01~0.20
C12：1	0.01	0.01	0.01	0.14	0.16	0.22	0.01~0.16	0.01~0.16
C14	0.02	0.03	0.04	0.33	0.36	0.43	0.05~0.37	0.03~0.36
C14：1	0.02	0.02	0.02	0.18	0.21	0.28	0.02~0.23	0.02~0.21
C14：2	0.00	0.01	0.01	0.03	0.04	0.05	0.01~0.04	0.01~0.04
C14OH	0.00	0.00	0.00	0.03	0.03	0.04	0~0.04	0~0.03
C16	0.30	0.51	0.62	6.98	7.58	9.18	0.65~7.02	0.51~7.58
C16：1	0.01	0.02	0.03	0.33	0.36	0.43	0.03~0.44	0.02~0.36
C16OH	0.00	0.00	0.00	0.03	0.04	0.05	0~0.05	0~0.04
C16：1OH	0.01	0.01	0.01	0.08	0.08	0.10	0.01~0.09	0.01~0.08
C18	0.13	0.20	0.25	1.88	2.08	2.60	0.27~1.89	0.20~2.08
C18：1	0.23	0.37	0.46	2.51	2.72	3.27	0.55~2.62	0.37~2.72
C18：2	0.04	0.06	0.07	0.55	0.60	0.82	0.06~0.65	0.06~0.60
C18：1OH	0.00	0.01	0.01	0.04	0.04	0.05	0.01~0.05	0.01~0.04
C18：2OH	0.00	0.00	0.01	0.03	0.03	0.04	0~0.04	0~0.03
C20	0.01	0.01	0.01	0.04	0.05	0.06	0.01~0.08	0~0.05
C22	0.00	0.00	0.00	0.01	0.02	0.02	0~0.02	0~0.02
C24	0.00	0.00	0.01	0.04	0.05	0.07	0~0.04	0~0.05
C26	0.00	0.01	0.01	0.04	0.05	0.06	0~0.04	0~0.05
C20：0-LPC	0.07	0.11	0.13	0.85	0.95	1.19	0.05~0.68	0.07~0.95
C22：0-LPC	0.04	0.07	0.08	0.49	0.56	0.79	0.02~0.45	0.07~0.56
C24：0-LPC	0.09	0.13	0.14	0.84	0.89	1.03	0.12~1.04	0.13~0.89
C26：0-LPC	0.05	0.08	0.09	0.55	0.59	0.73	0.05~0.79	0.08~0.59
C18OH	0.00	0.00	0.00	0.02	0.02	0.03	0~0.03	0~0.02

指标	百分位定位法						试剂盒参考范围	新参考范围
指标	P_0.1	P_0.5	P_1.0	P_99.0	P_99.5	P_99.9	试剂盒参考范围	新参考范围
ALA	115.60	139.17	150.46	497.83	529.09	612.49	136.41~541.37	140~600
ARG	0.98	1.14	1.24	30.54	37.42	55.09	1.33~34.41	1~38
ASA	0.02	0.04	0.05	0.99	1.14	1.56	0.01~1.09	0~1.1
CIT	4.19	4.91	5.31	23.78	27.08	36.93	5.85~28.99	4.9~27.0
GLN	101.29	136.59	161.23	905.12	958.07	1 117.58	129.46~950.47	100~1 100
GLU	86.54	109.44	123.90	678.48	732.20	859.08	114.14~469.10	90~850
GLY	125.91	152.19	169.58	707.30	766.98	894.84	191.89~870.58	126~900
LEU	54.91	66.20	71.76	249.04	265.07	310.31	69.03~222.81	55~265
MET	5.75	7.27	7.90	31.32	34.57	44.90	7.51~30.23	7.3~35.0
ORN	31.43	38.42	42.16	188.11	210.72	276.52	41.82~180.60	39~275
PHE	22.08	26.85	29.07	84.78	90.95	114.21	23.98~80.81	22~90
PRO	55.04	71.43	77.91	250.29	270.41	316.56	81.37~257.16	55~316
SA	0.00	0.00	0.00	0.60	0.74	0.99	0~0.71	0~0.74
TYR	23.18	29.71	32.86	186.88	214.38	294.53	30.54~232.96	23~294
VAL	48.04	57.11	61.35	208.92	227.05	276.60	65.59~211.08	48~230
ADO	0.24	0.30	0.34	3.54	4.07	5.03	0.15~2.89	0.15~3.50
D-ADO	0.00	0.00	0.00	0.07	0.08	0.10	0~0.06	0~0.08
C0	7.44	9.90	10.92	57.20	65.00	91.54	10.08~57.80	9.9~65.0
C2	2.62	4.94	5.85	35.67	39.51	49.23	6.39~44.50	4.94~40.00
C3	0.30	0.47	0.57	4.70	5.33	6.66	0.65~6.04	0.47~5.33
C3DC+C4OH	0.02	0.03	0.04	0.28	0.32	0.46	0.03~0.34	0.02~0.32
C4	0.05	0.07	0.08	0.38	0.43	0.63	0.07~0.45	0.07~0.43
C4DC+C5OH	0.08	0.10	0.11	0.56	0.65	0.89	0.10~0.61	0.10~0.65
C5	0.03	0.04	0.04	0.23	0.27	0.41	0.03~0.27	0.03~0.27
C5：1	0.00	0.00	0.00	0.02	0.02	0.03	0~0.02	0~0.03
C5DC+C6OH	0.02	0.02	0.02	0.14	0.16	0.21	0.02~0.14	0.02~0.21
C6	0.01	0.01	0.01	0.08	0.09	0.13	0.01~0.09	0.01~0.09
C6DC	0.01	0.02	0.02	0.11	0.13	0.16	0.01~0.12	0.02~0.16
C8	0.02	0.02	0.02	0.11	0.13	0.18	0.02~0.12	0.02~0.13
C8：1	0.01	0.02	0.02	0.18	0.21	0.29	0.02~0.22	0.01~0.21
C10	0.01	0.02	0.02	0.15	0.17	0.23	0.02~0.21	0.02~0.17
C10：1	0.01	0.02	0.02	0.09	0.10	0.13	0.01~0.11	0.02~0.10
C10：2	0.00	0.00	0.00	0.02	0.02	0.03	0~0.02	0~0.02
C12	0.01	0.01	0.01	0.17	0.20	0.26	0.02~0.22	0.01~0.20
C12：1	0.01	0.01	0.01	0.14	0.16	0.22	0.01~0.16	0.01~0.16
C14	0.02	0.03	0.04	0.33	0.36	0.43	0.05~0.37	0.03~0.36
C14：1	0.02	0.02	0.02	0.18	0.21	0.28	0.02~0.23	0.02~0.21
C14：2	0.00	0.01	0.01	0.03	0.04	0.05	0.01~0.04	0.01~0.04
C14OH	0.00	0.00	0.00	0.03	0.03	0.04	0~0.04	0~0.03
C16	0.30	0.51	0.62	6.98	7.58	9.18	0.65~7.02	0.51~7.58
C16：1	0.01	0.02	0.03	0.33	0.36	0.43	0.03~0.44	0.02~0.36
C16OH	0.00	0.00	0.00	0.03	0.04	0.05	0~0.05	0~0.04
C16：1OH	0.01	0.01	0.01	0.08	0.08	0.10	0.01~0.09	0.01~0.08
C18	0.13	0.20	0.25	1.88	2.08	2.60	0.27~1.89	0.20~2.08
C18：1	0.23	0.37	0.46	2.51	2.72	3.27	0.55~2.62	0.37~2.72
C18：2	0.04	0.06	0.07	0.55	0.60	0.82	0.06~0.65	0.06~0.60
C18：1OH	0.00	0.01	0.01	0.04	0.04	0.05	0.01~0.05	0.01~0.04
C18：2OH	0.00	0.00	0.01	0.03	0.03	0.04	0~0.04	0~0.03
C20	0.01	0.01	0.01	0.04	0.05	0.06	0.01~0.08	0~0.05
C22	0.00	0.00	0.00	0.01	0.02	0.02	0~0.02	0~0.02
C24	0.00	0.00	0.01	0.04	0.05	0.07	0~0.04	0~0.05
C26	0.00	0.01	0.01	0.04	0.05	0.06	0~0.04	0~0.05
C20：0-LPC	0.07	0.11	0.13	0.85	0.95	1.19	0.05~0.68	0.07~0.95
C22：0-LPC	0.04	0.07	0.08	0.49	0.56	0.79	0.02~0.45	0.07~0.56
C24：0-LPC	0.09	0.13	0.14	0.84	0.89	1.03	0.12~1.04	0.13~0.89
C26：0-LPC	0.05	0.08	0.09	0.55	0.59	0.73	0.05~0.79	0.08~0.59
C18OH	0.00	0.00	0.00	0.02	0.02	0.03	0~0.03	0~0.02

参考范围	筛查（例）	初筛阳性（例）	筛查阳率（%）	召回（例）	召回率（%）	诊断（例）	发病率	阳性预测值（%）
试剂盒参考范围	29 882	984	3.29	748	76.02	11	1/2 717	1.47
新参考范围	54 302	1 879	3.46	1 716	91.33	27	1/2 011	1.57
总计	84 184	2 863	3.40	2 464	86.06	38	1/2 215	1.54

参考范围	筛查（例）	初筛阳性（例）	筛查阳率（%）	召回（例）	召回率（%）	诊断（例）	发病率	阳性预测值（%）
试剂盒参考范围	29 882	984	3.29	748	76.02	11	1/2 717	1.47
新参考范围	54 302	1 879	3.46	1 716	91.33	27	1/2 011	1.57
总计	84 184	2 863	3.40	2 464	86.06	38	1/2 215	1.54

IEM分类	疾病名称	MS/MS结果（μmol/L）	GC-MS结果（μmol/mmol Cr）	基因	位点
氨基酸代谢障碍	HPA	PKU：329.18↑；PHE/TYR：6.35↑		PAH	c.1315+6T>A杂合c.122C>T
	HPA	PKU：225.14↑；PHE/TYR：3.03↑		PAH	c.478C>T杂合c.320A>G
	HMet	MET：56↑；MET/PHE：1.41↑		MAT1A	c.754A>T杂合
	MUSD	VAL：387.94↑；LEU：2911.54↑；LEU/PHE：87.80↑；VAL/PHE：11.70↑	2-OH-IVA：4719.12↑；3-2-K-IVA：2502.43↑；4-2-K-3-M-VA：2991.07↑；2-K-ICA：11447.6↑	BCKDHB	c.658C>T杂合c.920dup
尿素循环障碍	CD	CIT：22.82↑	3-OHPLA：86.32↑；4-4-OHPPA：132.86↑	SLC25A13	c.852_855del纯合
	CD	CIT：374.54↑；MET：79.32↑	5-OHPLA：39.68↑；6-4-OHPPA：42.0↑	SLC25A13	c.615+5G>A杂合c.852_855del
	CD	CIT：36.78↑；	4-OHPLA：499.16↑；5-4-OHPPA：397.86↑	SLC25A13	c.1751-5_1751-4in杂合c.852_855del
	CD	CIT：23.82↑	4-OHPLA：499.16↑；5-4-OHPPA：397.86↑	SLC25A13	c.852_855del纯合
	CD	CIT：34.98↑	4-OHPLA：3127.28↑；5-4-OHPPA：1060.40↑	SLC25A13	c.852_855del杂合c.615+5G>A
脂肪酸代谢障碍	PCD	C0：6.09↓		SLC22A5	c.51C>G杂合c.92C>G
	PCD	C0：3.16↓		SLC22A5	c.51C>G纯合
	PCD	C0：7.88↓		SLC22A5	c.694A>G杂合+c.1064C>T杂合
	PCD	C0：5.96↓		SLC22A5	c.51C>G杂合+c.760C>T杂合
	PCD	C0：6.23↓		SLC22A5	c.51C>G杂合+c.415G>A杂合
	PCD	C0：2.80↓		SLC22A5	c.51C>G杂合+c.760C>T杂合
	PCD	C0：4.09↓		SLC22A5	c.51C>G杂合+c.760C>T杂合
	PCD	C0：6.16↓		SLC22A5	c.51C>G杂合+c.797C>T杂合
	PCD	C0：1.99↓		SLC22A5	c.839C>T杂合+c.1064C>T
	PCD	C0：5.01↓		SLC22A5	c.51C>G杂合+c.1400C>G杂合
	PCD	C0：6.79↓		SLC22A5	c.51C>G杂合+c.1400C>G杂合
	PCD	C0：8.89↓		SLC22A5	c.51C>G纯合
	PCD	C0：3.15↓		SLC22A5	c.51C>G杂合+c.338G>A杂合
	SCADD	C4：0.69↑；C4/C3：0.44↑	EMA：36.09↑	ACADS	c.322G>A杂合+c.625G>A杂合
	SCADD	C4：0.60↑；C4/C3：0.40↑		ACADS	c.431C>T杂合+c.625G>A杂合
	SCADD	C4：0.68↑；C4/C3：13.60↑		ACADS	c.322G>A杂合+c.625G>A杂合
	SCADD	C4：0.49↑；C4/C3：0.44↑		ACADS	c.322G>A杂合+c.625G>A杂合
	SCADD	C4：0.60↑；C4/C3 0.34↑	EMA：69↑	ACADS	c.322G>A杂合+c.625G>A杂合
	SCADD	C4：0.91↑；C4/C3：0.65↑		ACADS	c.322G>A杂合+c.1031A>G杂合
	CPTⅠ	C0：154.06↑；C16：0.18↓；C18：0.07↓	正常	CPT1A	c.1339C>T杂合+c.2246G>A杂合
	CACT	C0：5.31↓；C16：12.4↑；C18 2.51↑；C18：1 5.35↑	HAD：210.27；QctDA：180.85；DecA：83.29	SLC25A20	c.199-10T>G杂合+c.326+1G>A杂合
	GA-Ⅱ	C5DC：0.6↑；c8：0.65↑；C10：1.32↑；c12：1.14↑		ETFDH	c.250G>A杂合+c.353G>T杂合
有机酸代谢障碍	MCCD	C5OH：0.88↑	正常	MCCC2	c.914A>G杂合+c.903+1G>A杂合
	MCCD	C5OH：3.49↑；C5OH/C3：0.03↑	3MCG：91.57↑；3-OH-IVA：252.96↑	MCCC2	c.464G>A杂合+c.1538T>C杂合
	GA-Ⅰ	C5DC：2.28↑；C5DC/C8：45.60↑	GA：5010.17↑；2-OHGA：42.27↑	GCDH	c.1063C>T杂合+c.271+1G>A杂合
	GA-Ⅰ	C5DC：2.90↑；C5DC/C8：96.67↑	GA：1667.44↑	GCDH	c.881G>A杂合+c.1063C>T杂合
	SBCADD	C5：1.15↑；C5/C3：1.42↑	2-MBT-GLY：70.93	ACADSB	c.275C>G杂合+c.746del杂合
	SBCADD	C5：0.42↑；C5/C3：0.62↑	2-MBT-GLY：105.01	ACADSB	c.746del杂合+c.655G>A杂合
	SBCADD	C5：1.14↑；C5/C3：1.21↑	2-MBT-GLY：18.04	ACADSB	c.1165A>G杂合+c.655G>A杂合