Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders

Abigail Veldman; C Edel Arar; M B Gea Kiewiet; Els Voorhoeve; Martijn E T Dollé; Monique de Sain-van der Velden; Rose E Maase; Francjan J van Spronsen; Birgit Sikkema-Raddatz; M Rebecca Heiner-Fokkema

doi:10.1007/s11306-026-02486-6

Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders

Abigail Veldman
, C Edel Arar
, M B Gea Kiewiet
, Els Voorhoeve
, Martijn E T Dollé
, Monique de Sain-van der Velden
, Rose E Maase
, Francjan J van Spronsen
, Birgit Sikkema-Raddatz
, M Rebecca Heiner-Fokkema^*

^*Corresponding author for this work

Section Metabolic Diagnostics

Research output: Contribution to journal › Review article › peer-review

Abstract

INTRODUCTION: Next-generation sequencing (NGS) is gaining attention in newborn screening (NBS) for its ability to detect treatable genetic disorders, especially those without a biochemical footprint. However, NGS-NBS requires interpreting variants without phenotype information or family trio analysis. Biochemical tests, preferably in dried blood spots (DBS), are therefore useful to confirm the pathogenicity of variants identified by NGS-NBS and increase its specificity and sensitivity.

OBJECTIVES: We aimed to explore the potential of combined genetic-biochemical testing for 95 treatable Inherited Metabolic Disorders (IMD) considered eligible for NGS-NBS (100 genes) previously identified by our research group.

METHODS: We reviewed the Collaborative Laboratory Integrated Reports (CLIR) and carried out systematic literature reviews in PubMed and Embase to identify biochemical tests for 95 IMD. Biochemical tests conducted on DBS were differentiated from tests that require referral.

RESULTS: We identified DBS-biochemical tests for 72 of the 95 IMD (77/100 genes). DBS-based biochemical tests for 55 IMD (60 genes) are already implemented in NBS. For the other 23 IMD, biochemical tests in non-DBS specimens are reported, although some are less sensitive when measured at neonatal age in presymptomatic infants.

CONCLUSION: We present a comprehensive overview of current biochemical tests for 95 IMD. These tests can be used to confirm inconclusive NGS-NBS results, and combined genetic-biochemical testing is expected to improve both the negative and positive predictive values of NBS programs.

Original language	English
Article number	105
Journal	Metabolomics
Volume	22
Issue number	4
DOIs	https://doi.org/10.1007/s11306-026-02486-6
Publication status	Published - 25 Jun 2026

Keywords

Humans
Neonatal Screening/methods
Infant, Newborn
High-Throughput Nucleotide Sequencing/methods
Metabolic Diseases/genetics
Dried Blood Spot Testing/methods
Genetic Testing/methods
Metabolism, Inborn Errors/diagnosis

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Veldman, A., Arar, C. E., Kiewiet, M. B. G., Voorhoeve, E., Dollé, M. E. T., de Sain-van der Velden, M., Maase, R. E., van Spronsen, F. J., Sikkema-Raddatz, B., & Heiner-Fokkema, M. R. (2026). Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders. Metabolomics, 22(4), Article 105. https://doi.org/10.1007/s11306-026-02486-6

@article{c8fb51bc7ac74174928df3e4c1f9aa85,

title = "Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders",

abstract = "INTRODUCTION: Next-generation sequencing (NGS) is gaining attention in newborn screening (NBS) for its ability to detect treatable genetic disorders, especially those without a biochemical footprint. However, NGS-NBS requires interpreting variants without phenotype information or family trio analysis. Biochemical tests, preferably in dried blood spots (DBS), are therefore useful to confirm the pathogenicity of variants identified by NGS-NBS and increase its specificity and sensitivity.OBJECTIVES: We aimed to explore the potential of combined genetic-biochemical testing for 95 treatable Inherited Metabolic Disorders (IMD) considered eligible for NGS-NBS (100 genes) previously identified by our research group.METHODS: We reviewed the Collaborative Laboratory Integrated Reports (CLIR) and carried out systematic literature reviews in PubMed and Embase to identify biochemical tests for 95 IMD. Biochemical tests conducted on DBS were differentiated from tests that require referral.RESULTS: We identified DBS-biochemical tests for 72 of the 95 IMD (77/100 genes). DBS-based biochemical tests for 55 IMD (60 genes) are already implemented in NBS. For the other 23 IMD, biochemical tests in non-DBS specimens are reported, although some are less sensitive when measured at neonatal age in presymptomatic infants.CONCLUSION: We present a comprehensive overview of current biochemical tests for 95 IMD. These tests can be used to confirm inconclusive NGS-NBS results, and combined genetic-biochemical testing is expected to improve both the negative and positive predictive values of NBS programs.",

keywords = "Humans, Neonatal Screening/methods, Infant, Newborn, High-Throughput Nucleotide Sequencing/methods, Metabolic Diseases/genetics, Dried Blood Spot Testing/methods, Genetic Testing/methods, Metabolism, Inborn Errors/diagnosis",

author = "Abigail Veldman and Arar, \{C Edel\} and Kiewiet, \{M B Gea\} and Els Voorhoeve and Doll{\'e}, \{Martijn E T\} and \{de Sain-van der Velden\}, Monique and Maase, \{Rose E\} and \{van Spronsen\}, \{Francjan J\} and Birgit Sikkema-Raddatz and Heiner-Fokkema, \{M Rebecca\}",

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year = "2026",

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doi = "10.1007/s11306-026-02486-6",

language = "English",

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journal = "Metabolomics",

issn = "1573-3882",

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Veldman, A, Arar, CE, Kiewiet, MBG, Voorhoeve, E, Dollé, MET, de Sain-van der Velden, M, Maase, RE, van Spronsen, FJ, Sikkema-Raddatz, B & Heiner-Fokkema, MR 2026, 'Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders', Metabolomics, vol. 22, no. 4, 105. https://doi.org/10.1007/s11306-026-02486-6

TY - JOUR

T1 - Next-generation newborn screening

T2 - feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders

AU - Veldman, Abigail

AU - Arar, C Edel

AU - Kiewiet, M B Gea

AU - Voorhoeve, Els

AU - Dollé, Martijn E T

AU - de Sain-van der Velden, Monique

AU - Maase, Rose E

AU - van Spronsen, Francjan J

AU - Sikkema-Raddatz, Birgit

AU - Heiner-Fokkema, M Rebecca

PY - 2026/6/25

Y1 - 2026/6/25

N2 - INTRODUCTION: Next-generation sequencing (NGS) is gaining attention in newborn screening (NBS) for its ability to detect treatable genetic disorders, especially those without a biochemical footprint. However, NGS-NBS requires interpreting variants without phenotype information or family trio analysis. Biochemical tests, preferably in dried blood spots (DBS), are therefore useful to confirm the pathogenicity of variants identified by NGS-NBS and increase its specificity and sensitivity.OBJECTIVES: We aimed to explore the potential of combined genetic-biochemical testing for 95 treatable Inherited Metabolic Disorders (IMD) considered eligible for NGS-NBS (100 genes) previously identified by our research group.METHODS: We reviewed the Collaborative Laboratory Integrated Reports (CLIR) and carried out systematic literature reviews in PubMed and Embase to identify biochemical tests for 95 IMD. Biochemical tests conducted on DBS were differentiated from tests that require referral.RESULTS: We identified DBS-biochemical tests for 72 of the 95 IMD (77/100 genes). DBS-based biochemical tests for 55 IMD (60 genes) are already implemented in NBS. For the other 23 IMD, biochemical tests in non-DBS specimens are reported, although some are less sensitive when measured at neonatal age in presymptomatic infants.CONCLUSION: We present a comprehensive overview of current biochemical tests for 95 IMD. These tests can be used to confirm inconclusive NGS-NBS results, and combined genetic-biochemical testing is expected to improve both the negative and positive predictive values of NBS programs.

AB - INTRODUCTION: Next-generation sequencing (NGS) is gaining attention in newborn screening (NBS) for its ability to detect treatable genetic disorders, especially those without a biochemical footprint. However, NGS-NBS requires interpreting variants without phenotype information or family trio analysis. Biochemical tests, preferably in dried blood spots (DBS), are therefore useful to confirm the pathogenicity of variants identified by NGS-NBS and increase its specificity and sensitivity.OBJECTIVES: We aimed to explore the potential of combined genetic-biochemical testing for 95 treatable Inherited Metabolic Disorders (IMD) considered eligible for NGS-NBS (100 genes) previously identified by our research group.METHODS: We reviewed the Collaborative Laboratory Integrated Reports (CLIR) and carried out systematic literature reviews in PubMed and Embase to identify biochemical tests for 95 IMD. Biochemical tests conducted on DBS were differentiated from tests that require referral.RESULTS: We identified DBS-biochemical tests for 72 of the 95 IMD (77/100 genes). DBS-based biochemical tests for 55 IMD (60 genes) are already implemented in NBS. For the other 23 IMD, biochemical tests in non-DBS specimens are reported, although some are less sensitive when measured at neonatal age in presymptomatic infants.CONCLUSION: We present a comprehensive overview of current biochemical tests for 95 IMD. These tests can be used to confirm inconclusive NGS-NBS results, and combined genetic-biochemical testing is expected to improve both the negative and positive predictive values of NBS programs.

KW - Humans

KW - Neonatal Screening/methods

KW - Infant, Newborn

KW - High-Throughput Nucleotide Sequencing/methods

KW - Metabolic Diseases/genetics

KW - Dried Blood Spot Testing/methods

KW - Genetic Testing/methods

KW - Metabolism, Inborn Errors/diagnosis

U2 - 10.1007/s11306-026-02486-6

DO - 10.1007/s11306-026-02486-6

M3 - Review article

C2 - 42348032

SN - 1573-3882

VL - 22

JO - Metabolomics

JF - Metabolomics

IS - 4

M1 - 105

ER -

Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders

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Keywords

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