Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry
Abstract
:1. Introduction
2. Materials and Methods
2.1. Recruitment and Sample Collection
2.2. Panel of Screened Disorders
2.3. Expended NBSs by MS/MS
2.4. NBS by NGS
2.5. Diagnosis
2.6. Statistical Analysis
3. Results
3.1. Performance of NBS by NGS Combined with MS/MS
3.2. Assessment of NGS as a First-Tier Screening Test
3.3. Assessment of MS-MS as a First-Tier Screening Test
3.4. Biochemical and Molecular Characteristics of the Diagnosed Patients
3.5. Carrier Frequencies and Geographical Distribution of Targeted Genes
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
MMA | Methylmalonic academia |
cblC-MMA | Methylmalonic academia, Cobalamin C defect |
cblA-MMA | Methylmalonic acidemia, Cobalamin A defect |
PCD | Primary carnitine deficiency |
PKU | Phenylketonuria |
SCADD | Short chain acyl-CoA dehydrogenase deficiency |
IBD | Isobutyryl-CoA dehydrogenase deficiency |
NICCD | Citrin deficiency |
MCAD | Medium-chain acyl-CoA dehydrogenase deficiency |
CPTII | Carnitine palmitoyltransferase II deficiency |
MSUD | Maple syrup urine disease |
MSUD (type II) | Maple syrup urine disease, type II |
MADD | Multiple acyl-CoA dehydrogenase deficiency |
OTCD | Ornithine transcarbamylase deficiency |
SH | Shanghai Xinhua Hospital |
GZ | Guangzhou Women and Children’s Medical Center |
JN | Jinan Maternal and Child Health Care Hospital |
SJZ | Shijiazhuang Maternal and Child Health Care Hospital |
CQ | Chongqing Maternal and Child Health Care Hospital |
YN | First People’s Hospital of Yunnan Province |
NMG | Inner Mongolia Maternal and Child Health Care Hospital |
HN | Hainan Women and Children’s Medical Center |
P | Pathogenic |
LP | Likely pathogenic |
VUS | Variant of uncertain significance or unclassified |
Het | Heterozygous |
Hom | Homozygous |
AR | Autosomal recessive |
NBS | Newborn screening |
NGS | Next-generation sequencing |
IEMs | Inborn errors of metabolism |
MS/MS | Tandem mass spectrometry |
DBS | Dried blood spots |
PPV | Positive predictive value |
References
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Disease Name | Gene | Diagnosed Cases | Incidence Rate | Carrier Frequencies |
---|---|---|---|---|
cblC-MMA | MMACHC | 5 | 1/5920 | 1/52 |
PCD | SLC22A5 | 5 | 1/5920 | 1/63 |
PKU | PAH | 3 | 1/9867 | 1/42 |
SCADD | ACADS | 2 | 1/14801 | 1/127 |
IBD | ACAD8 | 2 | 1/14801 | 1/211 |
NICCD | SLC25A13 | 1 | 1/29,601 | 1/55 |
MCAD | ACADM | 1 | 1/29,601 | 1/251 |
CPTII | CPT2 | 1 | 1/29,601 | 1/580 |
cblA-MMA | MMAA | 1 | 1/29,601 | 1/1139 |
MSUD (type II) | DBT | 1 | 1/29,601 | 1/1480 |
MADD | ETFA 1 | 1 | 1/29,601 | / |
Total | 23 | 1/1287 |
MS/MS Screening | Genetic Screening | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Units | Neonates | Positive Cases | Number of Recalls (Recall Rate) | Confirmed Cases | PPV | False Negative Cases | Confirmed Disease | Positive Cases | Number of Recalls (Recall Rate) | Confirmed Cases | PPV | False Negative Cases | Confirmed Disease |
SH | 4888 | 47 | 41 (87.2%) | 1 | 2.44 | 0 | MMA | 1 | 1 (100%) | 1 | 100 | 0 | MMA |
GZ | 4813 | 50 | 47 (94%) | 4 | 8.51 | 1 | MMA, PCD (2), MADD | 5 | 5 (100%) | 4 | 80 | 1 | MMA, NICCD, PCD (2) |
JN | 4797 | 149 | 138 (92.6%) | 6 | 4.35 | 0 | MMA (2), IBD, CPTII, PCD, MCAD | 6 | 6 (100%) | 4 | 66.67 | 2 | MMA (2), PCD, MCAD |
SJZ | 4899 | 67 | 65 (97.0%) | 2 | 3.08 | 0 | PKU, MSUD | 1 | 1 (100%) | 1 | 100 | 1 | PKU |
CQ | 2988 | 30 | 22 (73.3%) | 2 | 9.09 | 0 | PKU, PCD | 3 | 3 (100%) | 1 | 33.33 | 1 | PKU |
YN | 3006 | 43 | 40 (93.0%) | 2 | 5.00 | 1 | SCADD, IBD | 3 | 3 (100%) | 3 | 100 | 0 | MMA, SCADD, IBD |
NMG | 3233 | 113 | 36 (31.86%) | 2 | 5.56 | 0 | PKU, MMA | 3 | 3 (100%) | 2 | 66.67 | 0 | PKU, MMA |
HN | 977 | 8 | 8 (100%) | 2 | 25 | 0 | PCD, SCADD | 2 | 2 (100%) | 1 | 50 | 1 | PCD |
Total | 29601 | 507 | 397 (78.3%) | 21 | 5.29 | 2 | 9 (kinds) | 24 | 24 (100%) | 17 | 70.83 | 6 | 7 (kinds) |
Diagnosed Cases No. | Genetic/MS-MS Screening | Primary Screening Results (Cutoff) | Recall Review Results (Cutoff) | Genes | Exon | Nucleotide Change | Protein Change | ACMG | Zygosity | Disorders | Mode of Inheritance |
---|---|---|---|---|---|---|---|---|---|---|---|
Category | |||||||||||
P1 | +/+ | C3 15.19 (5) | 9.01 (5.5) | MMAA | EX2 | c.365T>C | p.Leu122Pro | LP | Hom | cblA-MMA | AR |
P2′ | +/+ | C3 4.4 (4.5), | C3 4.37 (4.5), | MMACHC | EX1 | c.80A>G | p.Gln27Arg | LP | Het | cblC-MMA | AR |
C3/C2 0.356 (0.2) | C3/C2 0.344 (0.2) | MMACHC | EX4E | c.482G>A | p.Arg161Gln | LP | Het | AR | |||
P3 | +/+ | C3 3.53 (5), Met8.36 (9), | C3 0.92 (5), Met7.17 (9), | MMACHC | EX1 | c.80A>G | p.Gln27Arg | LP | Het | cblC-MMA | AR |
C3/C2 0.18 (0.2) | C3/C2 0.25 (0.2) | MMACHC | EX4E | c.609G>A | p.Trp203 * | LP | Het | AR | |||
P4 | +/+ | C3 2.23 (4.5), | C3 3.64 (4.5), | MMACHC | EX1 | c.80A>G | p.Gln27Arg | LP | Het | cblC-MMA | AR |
C3/C2 0.235 (0.2) | C3/C2 0.44 (0.2) | MMACHC | EX4E | c.609G>A | p.Trp203 * | LP | Het | AR | |||
P5 1 | +/- | C3 1.99 (3.59) | C3 2.16 (4.5) | MMACHC | EX4E | c.482G>A | p.Arg161Gln | LP | Het | cblC-MMA | AR |
C3/C2 0.14 (0.2) | C3/C2 0.11 (0.22) | MMACHC | EX4E | c.565C>T | p.Arg189Cys | LP | Het | AR | |||
P6 | +/+ | C3 9.74 (4.8), C3/C2 0.57 (0.23) | C3 7.83 (4.8), C3/C2 0.96 (0.23) | MMACHC | EX4E | c.658_660delAAG | p.Lys220del | P | Hom | cblC-MMA | AR |
P7 | +/+ | Phe 276 (116), | Phe 393 (116), | PAH | EX3 | c.331C>T | (p.Arg111 *) | P | Het | PKU | AR |
Phe/Tyr 3.02 (1.5) | Phe/Tyr 4.57 (1.5) | PAH | IVS12 | c.1315+6T>A | LP | Het | AR | ||||
P8 | +/+ | Phe 606 (120), | Phe 10.89 (mg/dL) | PAH | EX5 | c.482T>C | p.Phe161Ser | LP | Het | PKU | AR |
Phe/Tyr 14.11 (1.5) | PAH | EX11 | c.1197A>T | p.V399V | P | Het | AR | ||||
P9 | +/+ | Phe 2.45 (mg/dL) (2.1) | Phe 166 (120), | PAH | EX6 | c.688G>A | p.Val230Ile | LP | Het | PKU | AR |
Phe/Tyr 1.88 (1.2) | PAH | EX12 | c.1238G>C | p.Arg413Pro | P | Het | AR | ||||
P10 | +/+ | C0 6.78 (10) | C0 10.09 (10) | SLC22A5 | EX1 | c.51C>G | p.Phe17Leu | LP | Hom | PCD | AR |
P11 | +/+ | C0 7.46 (10) | C0 4.64 (10) | SLC22A5 | EX2 | c.428C>T | p.Pro143Leu | P | Het | PCD | AR |
SLC22A5 | EX8 | c.1400C>G | p.Ser467Cys | P | Het | AR | |||||
P12 | +/+ | C0 8.82 (10) | C0 4.81 (10) | SLC22A5 | EX4 | c.760C>T | p.Arg254 * | P | Het | PCD | AR |
SLC22A5 | EX8 | c.1400C>G | p.Ser467Cys | P | Het | AR | |||||
P13 | +/+ | C0 5.16 (9) | C0 7.76 (9) | SLC22A5 | EX8 | c.1400C>G | p.Ser467Cys | P | Hom | PCD | AR |
P14 | +/+ | C4 2.8 (0.46) C4/C3 3.79 (0.4) | C4 1.98 (0.46) C4/C3 6.04 (0.4) | ACADS | EX9 | c.1031A>G | p.Glu344Gly | P | Hom | SCADD | AR |
P15 | +/+ | C4 2.08 (0.46) | C4 1.99 (0.46) | ACAD8 | EX3 | c.289G>A | p.Gly97Arg | LP | Het | IBD | AR |
C4/C3 4.1 (0.4) | C4/C3 2.02 (0.4) | ACAD8 | EX4 | c.413delA | p.Asn138Metfs * 36 | P | Het | AR | |||
P16 | +/+ | C8 3.64 (0.13), | C8 2.16 (0.13), | ACADM | IVS10 | c.946-1G>C | LP | Het | MCAD | AR | |
C8/C1015.8 (1.4) | C8/C10 12 (1.4) | ACADM | EX11 | c.1085G>A | p.Gly362Glu | LP | Het | AR | |||
P17 | +/- | Cit 20.13 (30) | Cit 449.85 (35) | SLC25A13 | EX16 | c.1638_1660dup | p.Ala554Glyfs * 17 | P | Het | NICCD | AR |
SLC25A13 | EX9 | c.852_855delTATG | p.Met285Profs * 2 | P | Het | AR | |||||
P18 | -/+ | Leu 1088 (270), | Leu 4182.3 (270), | DBT | EX2 | c.75_76delAT | p.Cys26Trpfs * 2 | P | Het | MSUD | AR |
Val 602 (269) | Val 998.6 (269) | DBT | EX11E | c.1359_1360delAG | p.Arg453Serfs * 3 | VUS | Het | AR | |||
P19 | -/+ | C4 1.19 (0.5) | C4 1.23 (0.5) | ACAD8 | EX4 | c.473A>G | p,Tyr158Cys | VUS | Het | IBD | AR |
ACAD8 | EX10 | c.1165C>T | p.Arg389Trp | VUS | Het | AR | |||||
P20 | -/+ | C4 0.9 (0.45) | C4 2.11 (0.45) | ACADS | EX3 | c.322G>A | p.Gly108Ser | LP | Het | SCADD | AR |
ACADS | EX6 | c.779G>T | p.Gly260Val | VUS | Het | AR | |||||
P21 | -/+ | C0 6.65 (9) | C0 8.96 (9) | SLC22A5 | EX8 | c.1400C>G | p.Ser467Cys | P | Het | PCD | AR |
SLC22A5 | EX3 | c.621G>T | p.Gln207His | VUS | AR | ||||||
P22 | -/+ | C12 1.18 (0.3), C14 2.52 (0.4), C16 25.1 (4.27), | C12 0.9 (0.33), C14 0.57 (0.4), | CPT2 | EX1 | c.125C>T | p.Thr42IIe | VUS | Het | CPTII | AR |
C18 5.82 (1.8), C18:1 8.94 (3) | C18:1 4.24 (3) | CPT2 | EX4 | c.1613delA | p.Tyr538Serfs * 5 | VUS | Het | AR | |||
P23 | -/+ | C4 2.19 (0.8), C5 3.11 (0.35), C6 1.14 (0.12), | C4 5.83 (0.8), C5 6.2 (0.35), C6 3.15 (0.12), | ETFA 1 | EX5 | c.369G>A | p.R122K | P | Het | MADD | AR |
C8 1.76 (0.16) | C8 5.2(0.16) | ETFA 1 | EX8 | c.659delC | p.S220Lfs * 6 | P | Het | AR |
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Tang, C.; Li, L.; Chen, T.; Li, Y.; Zhu, B.; Zhang, Y.; Yin, Y.; Liu, X.; Huang, C.; Miao, J.; et al. Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry. Int. J. Neonatal Screen. 2024, 10, 28. https://doi.org/10.3390/ijns10020028
Tang C, Li L, Chen T, Li Y, Zhu B, Zhang Y, Yin Y, Liu X, Huang C, Miao J, et al. Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry. International Journal of Neonatal Screening. 2024; 10(2):28. https://doi.org/10.3390/ijns10020028
Chicago/Turabian StyleTang, Chengfang, Lixin Li, Ting Chen, Yulin Li, Bo Zhu, Yinhong Zhang, Yifan Yin, Xiulian Liu, Cidan Huang, Jingkun Miao, and et al. 2024. "Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry" International Journal of Neonatal Screening 10, no. 2: 28. https://doi.org/10.3390/ijns10020028
APA StyleTang, C., Li, L., Chen, T., Li, Y., Zhu, B., Zhang, Y., Yin, Y., Liu, X., Huang, C., Miao, J., Zhu, B., Wang, X., Zou, H., Han, L., Feng, J., & Huang, Y. (2024). Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry. International Journal of Neonatal Screening, 10(2), 28. https://doi.org/10.3390/ijns10020028