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Next Generation Sequencing (NGS) in Newborn Screening
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Next Generation Sequencing (NGS) in Newborn Screening

A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (1 October 2021) | Viewed by 29701

Special Issue Editors

Dr. Mei Baker

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Guest Editor
Wisconsin State Laboratory of Hygiene, Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA
Interests: emerging technologies in newborn screening (real-time PCR, next generation sequencing, droplet digital PCR); severe combined immunodeficiency; spinal muscular atrophy; cystic fibrosis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Edwin Naylor

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Guest Editor
Consultant in Newborn Screening & Biochemical and Molecular Genetics, Department of Pediatrics (Genetics), Medical University of South Carolina, Charleston, SC, USA
Interests: newborn screening for duchenne and congenital muscular dystrophy including DNA confirmation using targeted NGS; prenatal and newborn screening for lead and other heavy metals (inductively coupled plasma-mass spectrometry); use of tandem mass spectrometry for newborn screening; development of 2nd-tier DNA confirmation for primary newborn screening
Special Issues, Collections and Topics in MDPI journals
Dr. Peter C. J. I. Schielen

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Guest Editor
Office of the International Society for Neonatal Screening, Reigerskamp 273, 3607 HP Maarssen, The Netherlands
Interests: (neonatal screening in) Europe; (neonatal screening and) the Wilson and Jungner criteria; lysosomal storage diseases; application of next generation sequencing in neonatal screening; inherited errors of metabolism; tandem mass spectrometry; genomics; artificial intelligence in neonatal screening; cystic fibrosis; screening policies and governance; quality assurance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, next generation sequencing (NGS) has secured a place in newborn screening. Early papers still described concepts, which especially invited a bio-ethical discussion on the pros and cons of the introduction of NGS, be it targeted or as a whole genome or exome approach. That did not stop the technical and epidemiological developments. Thus, these days, NGS technology is actually applied within newborn screening, almost exclusively in a second TIER setting, but this may change very soon. Developments concerning NGS in NBS have been quite astounding and we feel that it is time to determine where we are in this development, what is already in place, and what yet needs to be done.

This Special Issue on NGS in Newborn screening invites papers on the following:

  • Application of NGS in NBS in current practice
  • Proof of principle applications and retrospective studies
  • Prospective pilot studies
  • Application in current routine practice, both first TIER and second TIER
  • Contributions concerning medical ethical issues of NGS in NBS
  • QC QA issues/proficiency samples in NGS

Dr. Mei Baker
Dr. Peter C.J.I. Schielen
Prof. Dr. Edwin Naylor
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Neonatal Screening is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Related Special Issue

Published Papers (7 papers)

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11 pages, 267 KiB  
Article
Newborn Genetic Screening—Still a Role for Sanger Sequencing in the Era of NGS
by Silje Hogner, Emma Lundman, Janne Strand, Mari Eknes Ytre-Arne, Trine Tangeraas and Asbjørg Stray-Pedersen
Int. J. Neonatal Screen. 2023, 9(4), 67; https://doi.org/10.3390/ijns9040067 - 7 Dec 2023
Cited by 1 | Viewed by 1603
Abstract
In the Norwegian newborn screening (NBS) program, genetic testing has been implemented as a second or third tier method for the majority of NBS disorders, significantly increasing positive predictive value (PPV). DNA is extracted from dried blood spot (DBS) filter cards. For monogenic [...] Read more.
In the Norwegian newborn screening (NBS) program, genetic testing has been implemented as a second or third tier method for the majority of NBS disorders, significantly increasing positive predictive value (PPV). DNA is extracted from dried blood spot (DBS) filter cards. For monogenic disorders caused by variants in one single gene or a few genes only, Sanger sequencing has been shown to be the most time- and cost-efficient method to use. Here, we present the Sanger sequencing method, including primer sequences and the genetic test algorithms, currently used in the Norwegian newborn screening program. Full article
(This article belongs to the Special Issue Next Generation Sequencing (NGS) in Newborn Screening)
15 pages, 2537 KiB  
Article
Implementation of Hospital-Based Supplemental Duchenne Muscular Dystrophy Newborn Screening (sDMDNBS): A Pathway to Broadening Adoption
by Richard B. Parad, Yvonne Sheldon and Arindam Bhattacharjee
Int. J. Neonatal Screen. 2021, 7(4), 77; https://doi.org/10.3390/ijns7040077 - 15 Nov 2021
Cited by 20 | Viewed by 4718
Abstract
Duchenne muscular dystrophy (DMD) is not currently part of mandatory newborn screening, despite the availability of a test since 1975. In the absence of screening, a DMD diagnosis is often not established in patients until 3–6 years of age. During this time, irreversible [...] Read more.
Duchenne muscular dystrophy (DMD) is not currently part of mandatory newborn screening, despite the availability of a test since 1975. In the absence of screening, a DMD diagnosis is often not established in patients until 3–6 years of age. During this time, irreversible muscle degeneration takes place, and clinicians agree that the earlier therapy is initiated, the better the long-term outcome. With recent availability of FDA-approved DMD therapies, interest has renewed for adoption by state public health programs, but such implementation is a multiyear process. To speed access to approved therapies, we implemented a unique, hospital-based program offering parents of newborns an optional, supplemental DMD newborn screen (NBS) via a two-tiered approach: utilizing a creatine kinase (CK) enzyme assay coupled with rapid targeted next-generation sequencing (tNGS) for the DMD gene (using a Whole-Exome Sequencing (WES) assay). The tNGS/WES assay integrates the ability to detect both point mutations and large deletion/duplication events. This tiered newborn screening approach allows for the opportunity to improve treatment and outcomes, avoid the diagnostic delays, and diminish healthcare disparities. To implement this screening algorithm through hospitals in a way that would ultimately be acceptable to public health laboratories, we chose an FDA-approved CK-MM immunoassay to avoid the risks of false-negative/-positive results. Because newborn CK values can be affected due to non-DMD-related causes such as birth trauma, a confirmatory repeat CK assay on a later dried blood spot (DBS) collection has been proposed. Difficulties associated with non-routine repeat DBS collection, including the tracking and recall of families, and the potential creation of parental anxiety associated with false-positive results, can be avoided with this algorithm. Whereas a DMD diagnosis is essentially ruled out by the absence of detected DMD sequence abnormalities, a subsequent CK would still be warranted to confirm resolution of the initial elevation, and thus the absence of non-DMD muscular dystrophy or other pathologies. To date, we have screened over 1500 newborns (uptake rate of ~80%) by a CK-MM assay, and reflexed DMD tNGS in 29 of those babies. We expect the experience from this screening effort will serve as a model that will allow further expansion to other hospital systems until a universal public health screening is established. Full article
(This article belongs to the Special Issue Next Generation Sequencing (NGS) in Newborn Screening)
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14 pages, 561 KiB  
Article
Validation of a Custom Next-Generation Sequencing Assay for Cystic Fibrosis Newborn Screening
by Robert J. Sicko, Colleen F. Stevens, Erin E. Hughes, Melissa Leisner, Helen Ling, Carlos A. Saavedra-Matiz, Michele Caggana and Denise M. Kay
Int. J. Neonatal Screen. 2021, 7(4), 73; https://doi.org/10.3390/ijns7040073 - 2 Nov 2021
Cited by 17 | Viewed by 5219
Abstract
Newborn screening (NBS) for Cystic Fibrosis (CF) is associated with improved outcomes. All US states screen for CF; however, CF NBS algorithms have high false positive (FP) rates. In New York State (NYS), the positive predictive value of CF NBS improved from 3.7% [...] Read more.
Newborn screening (NBS) for Cystic Fibrosis (CF) is associated with improved outcomes. All US states screen for CF; however, CF NBS algorithms have high false positive (FP) rates. In New York State (NYS), the positive predictive value of CF NBS improved from 3.7% to 25.2% following the implementation of a three-tier IRT-DNA-SEQ approach using commercially available tests. Here we describe a modification of the NYS CF NBS algorithm via transition to a new custom next-generation sequencing (NGS) platform for more comprehensive cystic fibrosis transmembrane conductance regulator (CFTR) gene analysis. After full gene sequencing, a tiered strategy is used to first analyze only a specific panel of 338 clinically relevant CFTR variants (second-tier), followed by unblinding of all sequence variants and bioinformatic assessment of deletions/duplications in a subset of samples requiring third-tier analysis. We demonstrate the analytical and clinical validity of the assay and the feasibility of use in the NBS setting. The custom assay has streamlined our molecular workflow, increased throughput, and allows for bioinformatic customization of second-tier variant panel content. NBS aims to identify those infants with the highest disease risk. Technological molecular improvements can be applied to NBS algorithms to reduce the burden of FP referrals without loss of sensitivity. Full article
(This article belongs to the Special Issue Next Generation Sequencing (NGS) in Newborn Screening)
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17 pages, 936 KiB  
Article
Use of Molecular Genetic Analyses in Danish Routine Newborn Screening
by Allan Meldgaard Lund, Flemming Wibrand, Kristin Skogstrand, Marie Bækvad-Hansen, Niels Gregersen, Brage Storstein Andresen, David M. Hougaard, Morten Dunø and Rikke Katrine Jentoft Olsen
Int. J. Neonatal Screen. 2021, 7(3), 50; https://doi.org/10.3390/ijns7030050 - 26 Jul 2021
Cited by 14 | Viewed by 4232
Abstract
Historically, the analyses used for newborn screening (NBS) were biochemical, but increasingly, molecular genetic analyses are being introduced in the workflow. We describe the application of molecular genetic analyses in the Danish NBS programme and show that second-tier molecular genetic testing is useful [...] Read more.
Historically, the analyses used for newborn screening (NBS) were biochemical, but increasingly, molecular genetic analyses are being introduced in the workflow. We describe the application of molecular genetic analyses in the Danish NBS programme and show that second-tier molecular genetic testing is useful to reduce the false positive rate while simultaneously providing information about the precise molecular genetic variant and thus informing therapeutic strategy and easing providing information to parents. When molecular genetic analyses are applied as second-tier testing, valuable functional data from biochemical methods are available and in our view, such targeted NGS technology should be implemented when possible in the NBS workflow. First-tier NGS technology may be a promising future possibility for disorders without a reliable biomarker and as a general approach to increase the adaptability of NBS for a broader range of genetic diseases, which is important in the current landscape of quickly evolving new therapeutic possibilities. However, studies on feasibility, sensitivity, and specificity are needed as well as more insight into what views the general population has towards using genetic analyses in NBS. This may be sensitive to some and could have potentially negative consequences for the NBS programme. Full article
(This article belongs to the Special Issue Next Generation Sequencing (NGS) in Newborn Screening)
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11 pages, 1299 KiB  
Project Report
Towards Next-Generation Sequencing (NGS)-Based Newborn Screening: A Technical Study to Prepare for the Challenges Ahead
by Abigail Veldman, Mensiena B. G. Kiewiet, Margaretha Rebecca Heiner-Fokkema, Marcel R. Nelen, Richard J. Sinke, Birgit Sikkema-Raddatz, Els Voorhoeve, Dineke Westra, Martijn E. T. Dollé, Peter C. J. I. Schielen and Francjan J. van Spronsen
Int. J. Neonatal Screen. 2022, 8(1), 17; https://doi.org/10.3390/ijns8010017 - 24 Feb 2022
Cited by 19 | Viewed by 5666
Abstract
Newborn screening (NBS) aims to identify neonates with severe conditions for whom immediate treatment is required. Currently, a biochemistry-first approach is used to identify these disorders, which are predominantly inherited meta1bolic disorders (IMD). Next-generation sequencing (NGS) is expected to have some advantages over [...] Read more.
Newborn screening (NBS) aims to identify neonates with severe conditions for whom immediate treatment is required. Currently, a biochemistry-first approach is used to identify these disorders, which are predominantly inherited meta1bolic disorders (IMD). Next-generation sequencing (NGS) is expected to have some advantages over the current approach, for example the ability to detect IMDs that meet all screening criteria but lack an identifiable biochemical footprint. We have now designed a technical study to explore the use of NGS techniques as a first-tier approach in NBS. Here, we describe the aim and set-up of the NGS-first for the NBS (NGSf4NBS) project, which will proceed in three steps. In Step 1, we will identify IMDs eligible for NGS-first testing, based on treatability. In Step 2, we will investigate the feasibility, limitations and comparability of different technical NGS approaches and analysis workflows for NBS, eventually aiming to develop a rapid NGS-based workflow. Finally, in Step 3, we will prepare for the incorporation of this workflow into the existing Dutch NBS program and propose a protocol for referral of a child after a positive NGS test result. The results of this study will be the basis for an additional analytical route within NBS that will be further studied for its applicability within the NBS program, e.g., regarding the ethical, legal, financial and social implications. Full article
(This article belongs to the Special Issue Next Generation Sequencing (NGS) in Newborn Screening)
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9 pages, 1024 KiB  
Commentary
Scalable Newborn Screening Solutions: Bioinformatics and Next-Generation Sequencing
by Nicole Ruiz-Schultz, Bryce Asay and Andreas Rohrwasser
Int. J. Neonatal Screen. 2021, 7(4), 63; https://doi.org/10.3390/ijns7040063 - 30 Sep 2021
Cited by 4 | Viewed by 3145
Abstract
Expansion of the newborn disorder panel requires the incorporation of new testing modalities. This is especially true for disorders lacking robust biomarkers for detection in primary screening methods and for disorders requiring genotyping or sequencing as a second-tier and/or diagnostic test. In this [...] Read more.
Expansion of the newborn disorder panel requires the incorporation of new testing modalities. This is especially true for disorders lacking robust biomarkers for detection in primary screening methods and for disorders requiring genotyping or sequencing as a second-tier and/or diagnostic test. In this commentary, we discuss how next-generation sequencing (NGS) methods can be used as a secondary testing method in NBS. Additionally, we elaborate on the importance of genomic variant repositories for the annotation and interpretation of variants. Barriers to the incorporation of NGS and bioinformatics within NBS are discussed, and ideas for a regional bioinformatics model and shared variant repository are presented as potential solutions. Full article
(This article belongs to the Special Issue Next Generation Sequencing (NGS) in Newborn Screening)
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9 pages, 4351 KiB  
Case Report
Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant
by Kanokwan Sriwattanapong, Kitiwan Rojnueangnit, Thanakorn Theerapanon, Chalurmpon Srichomthong, Thantrira Porntaveetus and Vorasuk Shotelersuk
Int. J. Neonatal Screen. 2021, 7(1), 9; https://doi.org/10.3390/ijns7010009 - 5 Feb 2021
Cited by 2 | Viewed by 3250
Abstract
A variant in the POLG gene is the leading cause of a heterogeneous group of mitochondrial disorders. No definitive treatment is currently available. Prenatal and newborn screening have the potential to improve clinical outcome of patients affected with POLG-related disorders. We reported [...] Read more.
A variant in the POLG gene is the leading cause of a heterogeneous group of mitochondrial disorders. No definitive treatment is currently available. Prenatal and newborn screening have the potential to improve clinical outcome of patients affected with POLG-related disorders. We reported a 4-month-old infant who presented with developmental delay, fever, and diarrhea. Within two weeks after hospital admission, the patient developed hepatic failure and died. Liver necropsy demonstrated an extensive loss of hepatocytes and bile duct proliferations. Trio-whole exome sequencing identified that the patient was compound heterozygous for a novel frameshift variant c.3102delG (p.Lys1035Serfs*59) and a common variant c.3286C>T (p.Arg1096Cys) in POLG (NM_002693.3) inherited from the mother and father, respectively. The c.3102delG (p.Lys1035Serfs*59) was a null variant and classified as pathogenic according to the American College of Medical Genetics and Genomics Standards and Guidelines. Prenatal genetic screenings using rapid whole exome sequencing successfully detected the heterozygous c.3286C>T variant in the following pregnancy and the normal alleles in the other one. Both children had been healthy. We reviewed all 34 cases identified with the POLG c.3286C>T variant and found that all 15 compound heterozygous cases had two missense variants except our patient who had the truncating variant and showed the earliest disease onset, rapid deterioration, and the youngest death. All homozygous cases had disease onset before age 2 and developed seizure. Here, we report a novel POLG variant expanding the genotypic spectrum, demonstrate the successful use of exome sequencing for prenatal and neonatal screenings of POLG-related disorders, and show the genotype–phenotype correlation of the common c.3286C>T variant. Full article
(This article belongs to the Special Issue Next Generation Sequencing (NGS) in Newborn Screening)
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