As approximately 37% of critically ill newborn genomes identify a causal genetic disease, researchers and science companies are using whole genome sequencing (WGS) to develop new programmes and tools.

“Many of these genetic conditions often manifest in newborn babies and children, presenting complex symptoms difficult to attribute to a specific genetic cause,” says Professor Peter Bauer, Chief Medical and Genomic Officer at Centogene, a rare disease company.

In 2019, the North Carolina Newborn Exome Sequencing for Universal Screening study found that genome-based results focusing on age of onset or timing of interventions can help parents and physicians make decisions about the use of genomic sequencing for newborn screening and the disclosure of results.

In the UK, the government has made a multi-million-pound commitment to speed up screening. In December 2022, the National Health Service (NHS) announced a £175 million investment into genomic-based healthcare research led by Genomics England. The funding and innovation, which focuses on developing rapid WGS for children and babies, forms part of the UK’s strategy for embedding genomics in the NHS over the next five years to accelerate UK genomic medicine.

The uniqueness of newborn testing

Genomics within newborns raises several complexities, requiring specific considerations from medical device and technology companies when testing for severe genetic diseases. As newborns cannot express what they feel, medical practitioners have no symptoms to guide them. There is also no information about disease history or progression, making diagnosis more difficult.

“Newborns go from healthy to critical illness much, much faster than older children or adults, so we need answers immediately,” says Dr Stephen Kingsmore, President and CEO of Rady Children's Institute for Genomic Medicine.

Newborn responses to illness are much more stereotyped than adults as many of their organ systems are just starting to work. As a result, their “responses to disease are often the same despite having different causes, again making diagnosis more difficult,” Kingsmore adds.

Genome screening

Progress in genome screening is vital. At birth, much of a baby’s genome is used for the first time. Until delivery, their mother’s genome has been compensating, meaning genetic diseases are much more prevalent in newborns than in any other age group.

“The genome is the code of life, the instructions for being an individual human,” says Kingsmore. It is six billion DNA letters, continued within a four-letter code. Three letters are the code for an amino acid, and a string of amino acids creates a protein. There are 10,000 genetic diseases, 20,000 genes and around 200,000 proteins, Kingsmore relays.

For genetic disorders, the genome is the ideal single tool for detection. Since the genome is fixed, it can be searched at birth. “Screening by genome sequencing means that all 10,000 genetic diseases could potentially be screened for,” says Kingsmore. At birth, current understanding indicates there are about 700 disorders that should be screened for.

Traditional screening tools

Newborn screening started in the late 1960s, and today, 140 million babies worldwide receive newborn screening yearly, Kingsmore says. Depending on the country or region, between 1 and 80 disorders are tested for.

“Screening is only performed for severe, early childhood onset diseases for which effective treatments exist and for disorders where early treatment will result in better outcomes than later treatment,” Kingsmore confirms.

Most tests are performed on dried blood spots obtained by a heel prick. Traditional methods to test genetic conditions in babies and children include targeted gene sequencing, Chromosomal Microarray Analysis (CMA) and various specialised tests for specific genetic disorders. National newborn screening programmes are also available, which use mass spectrometric assays to identify a limited number of early-onset, treatable conditions.

“While these methods have their merits, they often have limited scope and may miss certain genetic variants that can be crucial in the diagnostic process,” says Bauer.

A genome sequencing system

A genome sequencing system decodes, analyses and interprets the genome code, identifying five million variants in each genome. “We analyse those changes and the clinical features observed in the newborn to identify whether he or she has one of the 10,000 genetic diseases,” says Kingsmore.

“We anticipate that we will identify a genetic disease in 1- 5% of newborns depending on the scope of testing – this is about 50-100 times what is detected currently,” Kingsmore adds. In addition, parents could potentially ask for broader testing, and parents and physicians could go back to the genome sequence across the lifespan to look for other disorders.

“WGS is the most comprehensive test, which captures a more complete picture of the entire genome and disease-causing variants at the beginning of a medical journey,” says Bauer.

Newborn screening research and development

About 15 groups worldwide are undertaking clinical trials to understand the screening potential of genomic systems. Rady Children's Institute for Genomic Medicine’s programme Begin Newborn Genome Sequencing (BeginNGS) is a consortium of 30 organisations. The programme focuses on building a test for 700-plus disorders that will cost around $200. It will scale to over four million newborns per year and will have a positive predictive value of more than 50%. It focuses on building infrastructure around the test so the healthcare system can cope with the positive results and translate them into timely treatments.

The programme has started its first prospective clinical trial for 434 disorders. It has completed retrospective studies of BeginNGS for 388 disorders in approximately 450,000 individuals, including the UK Biobank population, and has “shown that the test is highly effective”, Kingsmore says.

Science and technology companies are also developing innovations in the genomic field. In April 2023, Centogene launched its enhanced Next Generation Sequencing (NGS)-based assay CentoGenome, serving as a first-line test to capture an in-depth picture of the genome and accelerate access to potential treatment options. The tool tests for rare and neurodegenerative disorders in a single assay and strives to enable clinicians to uncover the underlying genetic factors contributing to these diseases and enable more precise diagnoses.

Global collaboration

Rady Children's Institute for Genomic Medicine confirms it interacts frequently with Genome England.“We share our plans and thinking and experiences,” Kingsmore says before continuing, “We have a shared interest in proving the value of genome-based screening”.

Centogene aims to shorten the diagnostic journey experienced by patients and their families and reduce the time and resources required to reach a conclusive diagnosis. “We aspire to contribute to a world healed of all rare and neurodegenerative diseases and being able to truly understand a given disease is at the core of that,” Bauer adds.