Beyond biochemical newborn screening: Overview of genome and exome sequencing

Dr Madhuri Hegde, FACMG – SVP and Chief Scientific Officer, Revvity highlights that two prominent methods in this new era of genomics are Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES), and each offers unique advantages in early disease detection

In the world of healthcare, newborn screening (NBS) plays a vital role in identifying and managing genetic disorders that may affect infants from the very beginning of their lives. This proactive approach also significantly reduces healthcare costs and contributes to better health outcomes for populations. In India, where thousands of babies are born with rare genetic diseases each year, the need for advanced diagnostic solutions in newborn screening has never been more pressing.¹

Traditional NBS methods have long relied on biochemical tests to identify a limited number of well-known genetic conditions. However, recent technological breakthroughs have led to the next generation of genomics, offering hyper-personalised, evidence-based treatment and management solutions. Two prominent methods in this new era of genomics are Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES), and each offers unique advantages in early disease detection.

WGS is a powerful technique that analyses an individual’s entire genetic code, covering not only coding regions but also non-coding regions that may hold crucial information about disease risk. This is an unbiased approach that can detect a wide range of disorders caused by point mutations, copy number changes and/or repeat expansions.

As it offers a wide coverage in detecting different variations of genetic disorders for newborns, its accessibility could lead to the early detection of diseases that would have gone unnoticed by traditional biochemical tests, potentially transforming the lives of children born with treatable genetic disorders. The earlier such genetic disorders are detected and diagnosed, the more likely it is that timely intervention will be possible to prevent disability or other long-term health effects.

In contrast to WGS, WES analyses only the protein-coding regions of an individual’s DNA. This is a more disease-centric approach, using a panel of well-known clinically relevant genes. While this method has its advantages, it is important to note that certain genetic variations affecting gene function and protein production can occur outside of these coding regions. ~15 per cent of reported disease mutations in the Human Gene Mutation database are outside of the coding regions of the genome.

A recent study conducted by Revvity Omics assessed these two proactive newborn screening approaches for screening genetic risks.² The study revealed that when a group of seemingly healthy children underwent screening using WGS, 8.2 per cent of them were found to be at risk of developing pediatric-onset diseases. Among these, 3.9 per cent were at almost 100 per cent risk of developing identified disorders. In contrast, when the children underwent screening using an exome-based panel of 268 genes, only 2.1 per cent of them were found to be at risk of developing a pediatric-onset genetic condition – a significantly lower rate.

These conditions would thus have remained undetected if a more restricted gene panel had been employed. When compared to WGS, a gene panel that is limited in scope would have only identified approximately one-fifth of the high penetrance conditions, many of which are neurodevelopmental disorders that could benefit from early interventions. This highlights the likely advantages of using comprehensive sequencing methods like WGS – which offers a holistic view of an individual’s genetic makeup, thus potentially identifying novel mutations and rare conditions. While WES is more targeted, it may miss crucial information residing in non-coding regions.

We must also acknowledge that both genome and exome sequencing approaches do come with a set of challenges that are important to address. Data analysis complexity and interpretation of variants of uncertain significance are among them. These challenges may be particularly relevant to the Indian healthcare system, keeping in mind the country’s population diversity.

As our understanding of genomic sequencing and its implications in diagnostics evolves, it is important for us to continue to conduct studies that inform the development of screening programs and diagnostic tools. The adoption of these advanced diagnostic tools should go hand in hand with the collaboration between health authorities and the scientific community to ensure that real-world practices align with the latest findings in genomics and healthcare.