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Genetic Newborn Screening
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Genetic Newborn Screening

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 November 2024) | Viewed by 17313

Special Issue Editors

Dr. Hisahide Nishio

E-Mail Website
Guest Editor
Faculty of Rehabilitation, Kobe Gakuin University, Kobe, Japan
Interests: genetics; spinal muscular atrophy
Prof. Dr. Hiroyuki Awano

E-Mail Website
Guest Editor
Organization for Research Initiative and Promotion, Tottori University, Yonago, Japan
Interests: neuromuscular disorders; Duchenne/Becker muscular dystrophy; spinal muscular atrophy; newborn screening

Special Issue Information

Dear Colleagues,

Newborn screening (NBS) has been conventionally performed by measuring disease-specific biomarkers with advanced technologies (biomarker NBS). Recently, however, spinal muscular atrophy (SMA) has been screened using genetic analysis in the neonatal period (genetic NBS). The genetic NBS program will be widely spread in the near future.

Genetic NBS does not need to rely on disease-specific biomarkers. It means that the same analytical method can be used to find patients with genetic disorders. Genetic NBS contributes to the healthy development of children with various genetic disorders, as does biomarker NBS. Here, we demonstrate the advances in the genetic analysis of newborn screening.

This Special Issue will present new methodologies for genetic NBS systems, outcomes of early treatments for the patients identified by genetic NBS testing, the new target diseases of genetic NBS programs, the molecular pathological mechanisms newly identified by genetic NBS researchers and accurate epidemiological findings based on genetic NBS data. This Special Issue will also present the advances in biomarker NBS followed by the genetic analysis of NBS-positive patients.

The editorial office of Genes would like to collect papers on the medical aspects of genetic NBS, such as those mentioned above. We also welcome the papers on biomarker NBS followed by genetic analysis.

In this Special Issue, new genetic methods for the early diagnosis of diseases in infants will be discussed. However, infant disease and fetal disease are on a continuum. Thus, newborn screening (or neonatal diagnosis) and prenatal diagnosis are very close. For example, to detect chromosomal abnormalities in fetuses, non-invasive prenatal genetic testing (NIPT) is increasingly performed worldwide. This is a type of genetic screening performed on the baby in the mother's womb. We think about the scope of the Special Issue in this way. Therefore, we welcome submissions of papers related to prenatal diagnosis using genetic analysis and chromosome analysis.

In addition, we are now planning to invite physicians currently engaged in genetic newborn screening for SMA, or those working to introduce genetic newborn screening for SMA to their countries. Many researchers are eager to gather information on the reality of newborn screening for SMA across the globe.

Dr. Hisahide Nishio
Prof. Dr. Hiroyuki Awano
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. Genes is an international peer-reviewed open access monthly 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 2600 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.

Keywords

  • newborn screening program
  • genetic newborn screening
  • biomarker newborn screening
  • genetic analysis

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Published Papers (8 papers)

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12 pages, 471 KiB  
Article
A Modular Genetic Approach to Newborn Screening from Spinal Muscular Atrophy to Sickle Cell Disease—Results from Six Years of Genetic Newborn Screening
by Jessica Bzdok, Ludwig Czibere, Siegfried Burggraf, Natalie Pauly, Esther M. Maier, Wulf Röschinger, Marc Becker and Jürgen Durner
Genes 2024, 15(11), 1467; https://doi.org/10.3390/genes15111467 - 13 Nov 2024
Cited by 1 | Viewed by 1530
Abstract
Background/Objectives: Genetic newborn screening (NBS) has already entered the phase of common practice in many countries. In Germany, spinal muscular atrophy (SMA), severe combined immunodeficiency (SCID) and sickle cell disease (SCD) are currently a mandatory part of NBS. Here, we describe the experience [...] Read more.
Background/Objectives: Genetic newborn screening (NBS) has already entered the phase of common practice in many countries. In Germany, spinal muscular atrophy (SMA), severe combined immunodeficiency (SCID) and sickle cell disease (SCD) are currently a mandatory part of NBS. Here, we describe the experience of six years of genetic NBS including the prevalence of those three diseases in Germany. Methods: Samples and nucleic acids were extracted from dried blood spot cards, commonly used for NBS. A qPCR assay was used to detect disease-causing variants for SMA and SCD, and the detection of T-cell receptor excision circles (TRECs) was performed for SCID screening. Results: The results of the NBS of over 1 million newborns for SMA, approximately 770,000 for SCID and over 410,000 for SCD are discussed in detail. In these newborns, we have identified 121 cases of SMA, 15 cases of SCID and syndrome-based immunodeficiencies and 77 cases of SCD or β-thalassemia. Conclusions: The flexibility of multiplex qPCR is assessed as an effective tool for incorporating different molecular genetic markers for screening. The processing of dried blood spot (DBS) filter cards for molecular genetic assays and the assays are described in detail; turn-around times and cost estimations are included to give an insight into the processes and discuss further options for optimization. The identified cases are in the range expected for the total number of screened newborns, but present a more exact view on the actual prevalences for Germany. Full article
(This article belongs to the Special Issue Genetic Newborn Screening)
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9 pages, 998 KiB  
Article
A Unique Comprehensive Model to Screen Newborns for Severe Combined Immunodeficiency—An Ontario Single-Centre Experience Spanning 2013–2023
by Abdulrahman Al Ghamdi, Jessica Willett Pachul, Azhar Al Shaqaq, Meghan Fraser, Abby Watts-Dickens, Nicole Yang, Linda Vong, Vy H. D. Kim, Victoria Mok Siu, Anne Pham-Huy, Rae Brager, Brenda Reid and Chaim M. Roifman
Genes 2024, 15(7), 920; https://doi.org/10.3390/genes15070920 - 15 Jul 2024
Cited by 2 | Viewed by 1439
Abstract
Background: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder caused by critical defects of the immune system. Almost all cases are lethal if not treated within the first two years of life. Early diagnosis and intervention are thus essential for improving patient [...] Read more.
Background: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder caused by critical defects of the immune system. Almost all cases are lethal if not treated within the first two years of life. Early diagnosis and intervention are thus essential for improving patient outcomes. In 2013, Ontario became the first Canadian province to perform newborn screening (NBS) for SCID by T cell receptor excision circles (TRECs) analysis, a surrogate marker of thymic function and lymphocyte maturation. Methods: This retrospective study reports on nearly 10 years of NBS for SCID at a quaternary referral centre. Results: From August 2013 to April 2023, our centre’s densely populated catchment area flagged 162 newborns with low TRECs levels, including 10 cases with SCID. Follow-up revealed other causes of low TRECs, including non-SCID T cell lymphopenia (secondary/reversible or idiopathic causes, and syndromic conditions) and prematurity. A small number of cases with normal repeat TRECs levels and/or T cell subsets were also flagged. Province-wide data from around this period revealed at least 24 diagnosed cases of SCID or Leaky SCID. Conclusions: This is the first report of NBS outcomes in a Canadian province describing the causative genetic defects, and the non-SCID causes of a positive NBS for SCID. Full article
(This article belongs to the Special Issue Genetic Newborn Screening)
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8 pages, 224 KiB  
Article
Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions
by Carlos F. Mares Beltran, Christina G. Tise, Rebekah Barrick, Annie D. Niehaus, Rebecca Sponberg, Richard Chang, Gregory M. Enns and Jose E. Abdenur
Genes 2024, 15(7), 838; https://doi.org/10.3390/genes15070838 - 26 Jun 2024
Viewed by 1965
Abstract
The state of California (CA) added X-linked adrenoleukodystrophy (X-ALD) to newborn screening (NBS) in 2016 via the measurement of C26:0-lysophosphatidylcholine (C26:0-LPC) in a two-tier fashion, followed by sequencing of the ABCD1 gene. This has resulted in the identification of individuals with genetic conditions [...] Read more.
The state of California (CA) added X-linked adrenoleukodystrophy (X-ALD) to newborn screening (NBS) in 2016 via the measurement of C26:0-lysophosphatidylcholine (C26:0-LPC) in a two-tier fashion, followed by sequencing of the ABCD1 gene. This has resulted in the identification of individuals with genetic conditions beyond X-ALD that can also result in elevated C26:0-LPC by NBS. We describe the biochemical, molecular, and clinical characteristics of nine patients from two metabolic centers in California who screened positive by NBS for elevated C26:0-LPC between 2016 and 2022 and were ultimately diagnosed with a genetic condition other than X-ALD. Seven individuals were diagnosed with Zellweger spectrum disorder (ZSD) due to biallelic variants in PEX genes. One male was diagnosed with Klinefelter syndrome and one female was found to have an X chromosome contiguous gene deletion syndrome after the identification of a heterozygous VUS and hemizygous VUS variant in ABCD1, respectively. Patients with ZSD had significantly higher first- and second-tier C26:0-LPC levels compared to the two non-ZSD cases. Identification of children with ZSD and atypical patterns of ABCD1 variants is a secondary benefit of NBS for X-ALD, leading to earlier diagnosis, prompt therapeutic initiation, and more accurate genetic counseling. As screening for X-ALD continues via the measurement of C26:0-LPC, our knowledge of additional genetic conditions associated with elevated C26:0-LPC will continue to advance, allowing for increased recognition of other genetic disorders for which early intervention is warranted. Full article
(This article belongs to the Special Issue Genetic Newborn Screening)
13 pages, 2043 KiB  
Article
Establishing a Standardized DNA Extraction Method Using NaCl from Oral Mucosa Cells for Its Application in Imprinting Diseases Such as Prader–Willi and Angelman Syndromes: A Preliminary Investigation
by Letícia Lopes Cabral Guimarães da Fonseca, Danielle Nascimento Rocha, Hiago Azevedo Cintra, Luiza Loureiro de Araújo, Gabrielle Leal Monteiro dos Santos, Leonardo Lima de Faria, Margarida dos Santos Salú, Silvia Helena dos Santos Leite, Adriana Duarte Rocha, Maria da Conceição Borges Lopes, Igor Ribeiro Ferreira, Leonardo Henrique Ferreira Gomes and Letícia Cunha Guida
Genes 2024, 15(5), 641; https://doi.org/10.3390/genes15050641 - 18 May 2024
Cited by 2 | Viewed by 2241
Abstract
Background: Diagnosing imprinting defects in neonates and young children presents challenges, often necessitating molecular analysis for a conclusive diagnosis. The isolation of genetic material from oral swabs becomes crucial, especially in settings where blood sample collection is impractical or for vulnerable populations like [...] Read more.
Background: Diagnosing imprinting defects in neonates and young children presents challenges, often necessitating molecular analysis for a conclusive diagnosis. The isolation of genetic material from oral swabs becomes crucial, especially in settings where blood sample collection is impractical or for vulnerable populations like newborns, who possess limited blood volumes and are often too fragile for invasive procedures. Oral swab samples emerge as an excellent source of DNA, effectively overcoming obstacles associated with rare diseases. Methods: In our study, we specifically addressed the determination of the quality and quantity of DNA extracted from oral swab samples using NaCl procedures. Results: We compared these results with extractions performed using a commercial kit. Subsequently, the obtained material underwent MS–HRM analysis for loci associated with imprinting diseases such as Prader–Willi and Angelman syndromes. Conclusions: Our study emphasizes the significance of oral swab samples as a reliable source for obtaining DNA for MS–HRM analysis. NaCl extraction stands out as a practical and cost-effective method for genetic studies, contributing to a molecular diagnosis that proves particularly beneficial for patients facing delays in characterization, ultimately influencing their treatment. Full article
(This article belongs to the Special Issue Genetic Newborn Screening)
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13 pages, 944 KiB  
Article
Multiplex Real-Time PCR-Based Newborn Screening for Severe Primary Immunodeficiency and Spinal Muscular Atrophy in Osaka, Japan: Our Results after 3 Years
by Tomokazu Kimizu, Masatoshi Nozaki, Yousuke Okada, Akihisa Sawada, Misaki Morisaki, Hiroshi Fujita, Akemi Irie, Keiko Matsuda, Yuiko Hasegawa, Eriko Nishi, Nobuhiko Okamoto, Masanobu Kawai, Kohsuke Imai, Yasuhiro Suzuki, Kazuko Wada, Nobuaki Mitsuda and Shinobu Ida
Genes 2024, 15(3), 314; https://doi.org/10.3390/genes15030314 - 28 Feb 2024
Cited by 5 | Viewed by 2706
Abstract
In newborn screening (NBS), it is important to consider the availability of multiplex assays or other tests that can be integrated into existing systems when attempting to implement NBS for new target diseases. Recent developments in innovative testing technology have made it possible [...] Read more.
In newborn screening (NBS), it is important to consider the availability of multiplex assays or other tests that can be integrated into existing systems when attempting to implement NBS for new target diseases. Recent developments in innovative testing technology have made it possible to simultaneously screen for severe primary immunodeficiency (PID) and spinal muscular atrophy (SMA) using quantitative real-time polymerase chain reaction (qPCR) assays. We describe our experience of optional NBS for severe PID and SMA in Osaka, Japan. A multiplex TaqMan qPCR assay was used for the optional NBS program. The assay was able to quantify the levels of T-cell receptor excision circles and kappa-deleting recombination excision circles, which is useful for severe combined immunodeficiency and B-cell deficiency screening, and can simultaneously detect the homozygous deletion of SMN1 exon 7, which is useful for NBS for SMA. In total, 105,419 newborns were eligible for the optional NBS program between 1 August 2020 and 31 August 2023. A case each of X-linked agammaglobulinemia and SMA were diagnosed through the optional NBS and treated at early stages (before symptoms appeared). Our results show how multiplex PCR-based NBS can benefit large-scale NBS implementation projects for new target diseases. Full article
(This article belongs to the Special Issue Genetic Newborn Screening)
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12 pages, 941 KiB  
Article
Newborn Screening for Spinal Muscular Atrophy: A 2.5-Year Experience in Hyogo Prefecture, Japan
by Shoko Sonehara, Ryosuke Bo, Yoshinori Nambu, Kiiko Iketani, Tomoko Lee, Hideki Shimomura, Masaaki Ueda, Yasuhiro Takeshima, Kazumoto Iijima, Kandai Nozu, Hisahide Nishio and Hiroyuki Awano
Genes 2023, 14(12), 2211; https://doi.org/10.3390/genes14122211 - 14 Dec 2023
Cited by 7 | Viewed by 2444
Abstract
Newborn screening (NBS) for spinal muscular atrophy (SMA) is necessary, as favorable outcomes can be achieved by treatment with disease-modifying drugs in early infancy. Although SMA-NBS has been initiated in Japan, its clinical results have not been fully reported. We report the findings [...] Read more.
Newborn screening (NBS) for spinal muscular atrophy (SMA) is necessary, as favorable outcomes can be achieved by treatment with disease-modifying drugs in early infancy. Although SMA-NBS has been initiated in Japan, its clinical results have not been fully reported. We report the findings of the initial 2.5 years of a pilot SMA-NBS of approximately 16,000 infants conducted from February 2021 in Hyogo Prefecture, Japan. Clinical data of 17 infants who tested positive were retrospectively obtained from the NBS follow-up centers participating in this multicenter cohort observational study. Genetic testing revealed 14 false positives, and three infants were diagnosed with SMA. Case 1 had two copies of survival motor neuron (SMN) 2 and showed SMA-related symptoms at diagnosis. Case 2 was asymptomatic, with two copies of SMN2. Asymptomatic case 3 had four copies of SMN2 exon 7, including the SMN1/2 hybrid gene. Cases 1 and 2 were treated within 1 month and case 3 at 8 months. All the patients showed improved motor function scores and did not require respiratory support. The identification of infants with SMA via NBS and early treatment improved their motor and respiratory outcomes. Thus, implementation of SMA-NBS at a nationwide scale should be considered. Full article
(This article belongs to the Special Issue Genetic Newborn Screening)
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14 pages, 2203 KiB  
Article
Real-Time PCR-Based Screening for Homozygous SMN2 Deletion Using Residual Dried Blood Spots
by Yoshihiro Bouike, Makoto Sakima, Yuya Taninishi, Takanori Matsutani, Yoriko Noguchi, Ryosuke Bo, Hiroyuki Awano and Hisahide Nishio
Genes 2023, 14(12), 2159; https://doi.org/10.3390/genes14122159 - 29 Nov 2023
Viewed by 1773
Abstract
The survival motor neuron 2 (SMN2) gene is a recognized modifier gene of spinal muscular atrophy (SMA). However, our knowledge about the role of SMN2—other than its modification of SMA phenotypes—is very limited. Discussions regarding the relationship between homozygous SMN2 [...] Read more.
The survival motor neuron 2 (SMN2) gene is a recognized modifier gene of spinal muscular atrophy (SMA). However, our knowledge about the role of SMN2—other than its modification of SMA phenotypes—is very limited. Discussions regarding the relationship between homozygous SMN2 deletion and motor neuron diseases, including amyotrophic lateral sclerosis, have been mainly based on retrospective epidemiological studies of the diseases, and the precise relationship remains inconclusive. In the present study, we first estimated that the frequency of homozygous SMN2 deletion was ~1 in 20 in Japan. We then established a real-time polymerase chain reaction (PCR)-based screening method using residual dried blood spots to identify infants with homozygous SMN2 deletion. This method can be applied to a future prospective cohort study to clarify the relationship between homozygous SMN2 deletion and motor neuron diseases. In our real-time PCR experiment, both PCR (low annealing temperatures) and blood (high hematocrit values and low white blood cell counts) conditions were associated with incorrect results (i.e., false negatives and positives). Together, our findings not only help to elucidate the role of SMN2, but also aid in our understanding of the pitfalls of current SMA newborn screening programs for detecting homozygous SMN1 deletions. Full article
(This article belongs to the Special Issue Genetic Newborn Screening)
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24 pages, 2502 KiB  
Perspective
Integrated Approaches and Practical Recommendations in Patient Care Identified with 5q Spinal Muscular Atrophy through Newborn Screening
by Vanessa L. Romanelli Tavares, Rodrigo Holanda Mendonça, Maytê S. Toledo, Sônia M. Hadachi, Carmela M. Grindler, Edmar Zanoteli, Wilson Marques, Jr., Acary S. B. Oliveira, Paulo Breinis, Maria da P. A. Morita and Marcondes C. França, Jr.
Genes 2024, 15(7), 858; https://doi.org/10.3390/genes15070858 - 29 Jun 2024
Cited by 1 | Viewed by 1967
Abstract
In recent years, significant progress has been made in 5q Spinal Muscular Atrophy therapeutics, emphasizing the importance of early diagnosis and intervention for better clinical outcomes. Characterized by spinal cord motor neuron degeneration, 5q-SMA leads to muscle weakness, swallowing difficulties, respiratory insufficiency, and [...] Read more.
In recent years, significant progress has been made in 5q Spinal Muscular Atrophy therapeutics, emphasizing the importance of early diagnosis and intervention for better clinical outcomes. Characterized by spinal cord motor neuron degeneration, 5q-SMA leads to muscle weakness, swallowing difficulties, respiratory insufficiency, and skeletal deformities. Recognizing the pre-symptomatic phases supported by screening and confirmatory genetic tests is crucial for early diagnosis. This work addresses key considerations in implementing 5q-SMA screening within the Brazilian National Newborn Screening Program and explores Brazil’s unique challenges and opportunities, including genetic tests, time-to-patient referral to specialized centers, program follow-up, and treatment algorithms. We aim to guide healthcare professionals and policymakers, facilitating global discussions, including Latin American countries, and knowledge-sharing on this critical subject to improve the care for newborns identified with 5q SMA. Full article
(This article belongs to the Special Issue Genetic Newborn Screening)
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