What is Genomic Newborn Screening?

Newborn screening basics

Newborn screening (NBS) is one of the greatest success stories of preventive population health, and in Australia it saves hundreds of children from life-long disability or death each year. NBS aims to find babies affected by certain inherited diseases in the first few weeks of life so treatment that can be started early to prevent the disease from causing permanent harm. Shortly after birth, a small blood sample is taken from a heel-prick of a newborn and is tested in the laboratory by different biochemical assays to screen for up to 25 different inherited diseases. By using new genomic technology, it is now possible to expand the number of conditions by up to 10-fold in one assay.

Genomic newborn screening

Testing of a single gene is called genetic testing, while testing of multiple genes is called genomic testing. Sometimes the terms genetic and genomic are used interchangeably. 

There has been great interest in using genomics to expand newborn screening (NBS), as it would allow potentially hundreds of conditions to be screened by one test. The principle behind genomic NBS is to use the latest in DNA sequencing technology (called next-generation DNA sequencing) on a newborn bloodspot screening sample to determine the genetic code of hundreds or thousands of genes quickly and accurately. The DNA code is then analysed through computer algorithms and information databases to identify any disease-causing DNA sequences (or variations) that cause a gene to malfunction and lead to a disease.

Types of genomic newborn screening

Sequencing the entire genetic make-up of an individual (whole genome sequencing) is one approach to genomic newborn screening. Research projects in the US, UK, and Australia have investigated, or are currently investigating, whether whole genome sequencing of ~20,000 genes is a feasible method for NBS. Early results have been disappointing, with problems such as cost, ability to analyse and store information of an individual’s genome in a meaningful timeframe for NBS, and ethical concerns of sequencing the entire genome of a baby, being significant barriers for implementing whole genome sequencing in NBS programs. The same problems apply to whole exome sequencing, which is like whole genome sequencing except only a gene’s coding region is sequenced.

To date, there is no evidence that whole genome sequencing can be done to the scale needed for NBS programs in a clinically useful timeframe. Research in the area continues, but it is unlikely whole genome sequencing will be ready for NBS screening soon.

An alternative approach to whole genome sequencing is to use targeted gene sequencing (TGS), where only a carefully selected number of genes are sequenced. By only analysing the exons and clinically important non-coding regions of a panel of 50 to 200 genes, there are tremendous advantages compared to whole genome sequencing in regard to cost, test turnaround time, and ethical concerns. Unlike whole genome sequencing, the feasibility of integrating TGS into NBS programs has been demonstrated. Research has shown TGS to be scalable to the needs of NBS programs and can provide immense benefits to improving the clinical utility of NBS.

The difference between screening and diagnostic tests

When a test is used to confirm a diagnosis in an unwell individual, it is called a diagnostic test. If a newborn is unwell and in an intensive care unit and a genomic test is done, it is a diagnostic test to find the cause of why the child is sick.  It is not a screening test.

Screening tests are different. A screening test is an early detection test done on  a the person is who well at the time the test is done.  Screening tests are called predictive tests. If an individual has a genomic newborn screening test and well described disease-causing DNA variant in a gene that causes disease with high penetrance, it is almost certain the individual will have the disease but other diagnostic tests are done to to confirm the DNA result.

Other types of genomic tests

Genomic tests for medical purposes are stringently regulated to ensure accuracy and safety. Medical DNA testing is available for all stages of life and their use varies greatly, from helping parents make family planning decisions to diagnosing what type of cancer someone has. Other DNA tests which are not for medical decision making are sold commercially without direct medical oversight, and include ancestry testing, paternity testing, and non-accredited ‘lifestyle’ disease risk test’s (e.g. 23&Me).

Below are examples of some common tests that are used for medical purposes.

Reproductive carrier screening: Parents are tested before having children (or early in pregnancy) to see if they are a carrier for an inherited condition. Although a carrier for a condition does not clinically present with the condition, there is an increased risk of their biological child being born with a condition if both parents are carriers for the same condition. Couples who are carriers for a condition can opt for IVF to prevent the risk of their child from being born with the condition.

NIPT (Non invasive prenatal testing): During pregnancy at 10 weeks’ gestation, the baby is tested for 3 genetic conditions, including Down Syndrome. The assay is a low-pass whole genome sequencing assay designed to detect large chromosomal abnormalities. If the screen is positive, there is an option to terminate the pregnancy.

Diagnostic gene testing: If someone has signs and symptoms or other indications of an inherited disease, a genetic test may be performed to confirm a diagnosis. Typically, a single or a small number of genes known to cause the disease are sequenced. Identification of disease-causing DNA variants would confirm the diagnosis. Types of disease-causing variants include a single nucleotide variant (SNV), small insertion or deletion, complex variants such as indels, or large deletions or duplications (copy number variants).

Somatic cancer/oncology testing: A tumour biopsy is sequenced to determine if certain disease-causing DNA variants are found, which can then inform treatment using specialised therapeutics appropriate for the detected variant.

When will genomic newborn screening be ready to be implemented in population screening programs?

Genomic NBS is now ready to be implemented by NBS programs, as demonstrated by Genepath and collaborators in the landmark feasibility study published in 2023 in the leading laboratory medicine peer-reviewed journal Clinical Chemistry. A targeted gene sequencing approach for NBS has been shown to overcome the many implementation barriers associated with whole genome or whole exome sequencing, namely cost, scalability, and turnaround time. Innovative new sample tracking and data analysis software purpose-designed for handling the large sample numbers required by NBS programs each day, and refined protocols for semi-automated robotics laboratory procedures makes Genepath’s Atlas newborn genomic screening test ready to be implemented into NBS programs who seek to expand the number of conditions tested and to vastly improve the cost-effectiveness of their screening.