A close-up view of a screen with multicoloured graph lines created from the sequencing of dna

The key principles behind newborn genome screening

The Generation Study will explore the benefits and challenges of sequencing the genomes of 100,000 newborn babies

In our previous blog, we looked at the Generation Study, a collaboration between Genomics England and the NHS, that will look for rare genetic conditions where early treatment can be beneficial. In this blog, we examine the principles and screening parameters of the study.

Genomics England has published a list of 223 conditions that will be screened for by the study. These conditions were selected in accordance with four key principles, which were developed in consultation with clinicians, scientists, patients and the public. Each principle is summarised below.

Principle A

There is strong evidence that the genetic variant(s) causes the condition and can be reliably detected.

This principle covers the evidence base between a particular gene variant and the condition associated with it.

In many cases, a particular gene is known to be associated with whether or not a person has a particular condition, but there are many different possible variants within the same gene. Some have no effect, some are known to cause disease, and with others there is uncertainty. This last group are known as variants of uncertain significance (VUS).

Principle A makes it clear that VUS will not be tested for.

In terms of a condition being ‘reliably detected’, there may be a requirement for further testing (including non-genetic tests) to confirm whether a child has the condition.

Principle B

A high proportion of individuals who have the genetic variant(s) would be expected to have symptoms that would have a debilitating impact on quality of life if left undiagnosed.

This principle covers two main points: the impact of the condition, and its penetrance.

The impact of the condition is assessed, and only conditions where the symptoms have a ‘debilitating impact’ will be screened for. This rules out screening for genetic variants that cause only mild illness.

Additionally, the penetrance of the genetic variant is considered. Penetrance is a measure of the number of people who have a genetic variant who develop symptoms of the condition that is associated with that variant.

For example, not everyone who carries a BRCA1 or BRCA2 variant goes on to develop cancer. Depending on the precise variant, women who have a BRCA variant have up to a 70% chance of developing breast cancer in their lifetimes.

Principle B rules out screening for gene variants with low penetrance, where few children who are found to have the variant are likely to be affected.

Principle C

Early or pre-symptomatic intervention for the condition has been shown to lead to substantially improved outcomes in children, compared to intervention after the onset of symptoms.

The study will only look for genetic variants associated with conditions where early diagnosis can benefit the patient.

In practice, this will mean conditions where a treatment is available that can cure the condition, or delay onset, slow progression or modify the course of the disease. In addition, the treatment would normally need to start by age five to qualify.

Principle C rules out screening for conditions for which there is no effective treatment.

Principle D

Conditions screened for are only those for which the interventions are equitably accessible for all.

An effective treatment must be both available and accessible. This involves checking with regulatory bodies such as NICE, NHS clinical bodies and local integrated care boards, to ensure that any children diagnosed with the condition can access the treatment or care that will make a difference to their condition.

Condition D rules out screening for conditions where treatment is not available on the NHS, perhaps because they are expensive, experimental or unproven.

Looking to the future

Using the criteria within these four principles means that the study may adapt as science and medicine evolve. This could allow further conditions to be added in the future, for example, if NICE approves a new gene therapy for a previously untreatable condition, or when a VUS is reclassified as a harmful variant as new evidence emerges.

The principles also offer a model for deciding what conditions might be screened for in future if whole genome sequencing does become an integrated part of newborn screening across the NHS.

Please note: This article is for informational or educational purposes, and does not substitute professional medical advice.