Newborn screening: What advances are unlocking new medical interventions?

Newborn screening: What advances are unlocking new medical interventions?

By Fernanda Boni

Newborn screening (NBS) originated in the 1960s, when Dr. Robert Guthrie developed a blood test to identify a condition called Phenylketonuria shortly after birth. The success of this effort resulted in continuous advances in neonatal and prenatal screening.

Genetic testing expanded with the human genome mapping in 2003, enabling the identification of changes at the level of individual genes, parts of genes, or even single nucleotides. Since then, newborn screening evolved to a new level, permitting accurate knowledge of the genetic origin of metabolic disorders for correct management, especially in cases of critically ill newborns, giving insight for future customized treatment of anomalies in early life.

Genetic Testing
Fig: A Brief History of Genetic Testing

What is the current “state of the art” for newborn screening?

Karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray are the first-choice tests for the genetic screening of newborns as soon as a genetic abnormality is suspected. 

Chromosomal microarray is a modern technique that uses high sensitivity to detect microdeletions or clinically significant duplications in chromosomes. However, it cannot provide information about a specific gene, and it can take up to four weeks to receive test results. By using these conventional newborn screening techniques, larger genomic variations, such as deletions, duplications, and translocations, can be detected. 

Nonetheless, these methods are ineffective for observing changes in a single nucleotide or pair of bases. Thus, genetic tests have evolved into DNA sequencing-based techniques.

DNA sequencing is used to determine the sequence of DNA’s bases. It can be used for single gene testing, targeted sequencing of a selected number of genes (gene panel), sequencing between exons or protein-coding regions of the genome, or sequencing across all protein-coding and non-coding regions. 

For many years, Sanger sequencing was the gold standard for DNA sequencing. It is a reliable technique based on the random incorporation of chain-terminating dideoxynucleotides by DNA polymerase during replication and employing electrophoresis. But this method can only be used to look at small pieces of DNA and can’t find changes that only affect a few cells. 

The screening panel covers gaps and unmet needs:

Currently, newborn screening programs can investigate over 30 potentially fatal but potentially treatable diseases. About 6% of newborns are affected by genetic disorders and congenital anomalies, which are the leading causes of hospitalization and mortality. Approximately 6,000 disorders can be diagnosed through the use of DNA sequencing tests.

Still, they are limited to the second line of choice or the diagnostic investigation subsequent to the identification of a possible disorder, not being included in the conventional screening panel. Moreover, many of these tests can be performed even before birth, in the embryonic phase, allowing risk assessment, selection of early treatment/intervention, adequate management of pregnancy, and planning of the postnatal care requirements.

New therapies for progressive neurological and neuromuscular diseases such as Huntington’s disease, muscular dystrophies, adrenoleukodystrophy, fragile X syndrome, and spinal muscular atrophy are emerging. It is estimated that by 2030, there will be at least 60 new therapies for different diseases approved by the FDA. Including these severe “non-traditional” disorders and disorders that can manifest later in the screening panel program can make detection and diagnosis faster and more effective, reducing the impact on the quality of life of children and families.

Progress in genetic screening applied to the diagnosis:

Next-generation sequencing  (NGS) is a DNA screening technique that has expanded and become more adaptable as a result of advances in molecular biology. NGS techniques permit the simultaneous processing of numerous samples, and they are readily applicable from the evaluation of a few genes to the analysis of the entire genome.

In these techniques, DNA is extracted from the sample, fragmented, and marked for identification and sequencing. Using bioinformatics software and algorithms, the DNA pieces are then lined up and mapped to a human genome reference. 

Roche 454 (pyrosequencing), Illumina (Reversible Dye Terminator), Ion-torrent, PacBio, and Nanopore stand out among the commercial NGS platforms. These platforms differ in their sequencing engineering and chemistry configurations. However, they are all based on massively parallel sequencing via spatially separated clonally amplified DNA templates or single DNA molecules in a flow cell.

These different NGS approaches can help with everything from the identification of complex diseases caused by a combination of genetic and environmental factors to the assessment of the child’s susceptibility to developing bacterial infections and gluten intolerance.

The emergence of new technologies and equipment for NGS has further contributed to a significant decrease in the cost of these sequencing methods. Cost issues associated with the speed of processing results are the critical points for kicking off an era of personalized medicine, in which health professionals will routinely use the newborn’s genetic code to prevent and customize disease treatment.

In response to these emerging technologies, in the last decade, the possibility of performing prenatal genetic screening has become a reality.

Screening of genetic diseases during pregnancy:

Prenatal screening focuses on the early detection of pregnancy-related problems. NGS is one of the prenatal screening techniques that can detect aneuploidies (e.g., Down syndrome and Trisomy 21) or partial chromosomal alterations (duplications or deletions) in all chromosomes with a sensitivity above 95%. Preimplantation genetic diagnosis and monogenic diseases such as sickle cell anemia are better addressed by FISH.

Recently, these genetic tests have advanced to non-invasive methods, for example, by cell-free fetal DNA technique using maternal plasma. The size difference between the embryo and maternal DNA fragments allows for its distinction. To look at the fetal DNA, you can use real-time PCR with fluorescent probes, shotgun sequencing (Solexa or Illumina), or massive targeted parallel sequencing. 

If this kind of genetic screening is studied more, it may be possible to use targeted molecular interventions with specific drug therapies (pharmacogenetics) and to change cells, tissues, and organs physically and chemically. 

Future perspective for the early treatments of genetic disorders:

Genetic factors contribute to the etiology of 80% of children with rare diseases, and other contributing factors, including infections, account for the remaining cases. Advances in genetic technologies have made it possible to use targeted drugs, vitamin supplements or dietary restrictions, protein/enzyme replacement therapies, and stem cell transplantation to treat diseases that were once untreatable. 

In 2017, the FDA approved the first gene therapy in the United States for pediatric patients with a form of Acute Lymphoblastic Leukemia, the Kymriah®. In this therapy, the patient’s T cells are genetically modified to include a new gene that encodes a chimeric antigen receptor, programming the modified T cells to attack and kill the leukemic cells. Yescarta® and Zynteglo® are two other examples of approved gene therapies for large B-cell lymphoma and beta-thalassemia, respectively. 

Recently, new approaches to precision medicine have emerged, with gene therapies involving splicing modifiers and exon skipping protocols. In 2016, the Food and Drug Administration approved Eteplirsen, which is an exon-skipping drug that is used to treat Duchenne muscular dystrophy. Then Golodirsen was approved for the same application in 2019.

These drugs differ by the target exon of attack, as the disturbed mutations can cluster between the dystrophin exons 45 to 53. In this case, genetic screening, which is usually done by looking at blood samples, is the most important way to figure out the exact nature and location of the dystrophin gene mutation and choose the best treatment. 

These examples make it clear that developing effective treatments for genetic disorders, which result in serious pathologies, depends on knowledge of the molecular bases that cause this disease. In this way, advances in medical genetics and genomics are making early and accurate diagnoses (both prenatal and in newborns) possible and are getting us closer to personalized treatment

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