National DNA Day – Genetic testing in children for Familial Hypercholesterolaemia

25th April 2024

To mark National DNA Day, which takes place on 25th April, we’re raising the profile of Familial Hypercholesterolaemia (FH), a genetic condition that often goes undiagnosed. In the North East and North Cumbria, just 12%[1] of people with the condition are currently identified.

Without treatment, FH can lead to extremely high cholesterol levels and heart disease at a young age. However, if it is identified and treated early, the condition can be well managed.

As part of a national pilot, HI NENC leads the Child Parent Screening Service which tests toddlers for a ‘faulty gene’ causing FH. In pilot GP practices, parents are offered a heel prick blood test during their child’s one-year routine immunisation appointment to check their cholesterol level. If the level is above a specified level a sample is sent to one of seven Genomic Laboratory Hubs across the country to be analysed.

We spoke to Angela Cocklin, Clinical Scientist, and Stuart Gillies, Principal Clinical Scientist, who work at the North West Genomic Laboratory Hub. They tell us about their involvement in the analysis of genetic tests, including a recent milestone when they identified the first child with FH as part of this pilot.

What is the importance of identifying people with FH at an early age?

The NHS long term plan describes cardiovascular disease (CVD) as ‘the single biggest area where the NHS can save lives’. Key to achieving this is the early detection and treatment of individuals at risk of CVD. In the UK there are estimated to be over 100,000 individuals at risk of CVD due to elevated cholesterol levels caused by having the inherited genetic condition Familial Hypercholesterolaemia (FH).

FH is estimated to affect up to 1 in 250 people[2] and is widely reported to be under diagnosed. Most confirmed FH cases are due to genetic changes, termed ‘causative variants’, in either the LDLR, APOB or PCSK9 genes.

Cholesterol levels in individuals with an FH-causing variant are known to steadily increase from birth. Therefore, higher cholesterol levels can be detected in children who have a ‘faulty’ gene for FH before the onset of symptoms.

Intervention in an infant with an FH-causing variant before the age of 10 years has been shown to effectively reduce that individual’s risk of CVD to that of the general population.[3]

The identification of an FH-causing variant in the child also unlocks cascade testing in their relatives.  Notably, when you find a child with an FH-causing variant, one of their parents will also have the same FH-causing variant and thus be at risk of elevated cholesterol and CVD.

What is the Child-Parent Screening Service (CPSS) and how are Genomic Laboratory Hubs involved?

CPSS aims to identify infants at their routine immunisation visit, who are at a higher probability of carrying an FH-causing variant. By taking a heel prick blood sample, elevated cholesterol levels can be detected biochemically (TC levels ≥5.3mmol/L) and the remaining patient sample can be sent for genetic testing.

These blood samples are sent to one of seven NHS Genomic Laboratory Hubs (GLH) to be analysed. If an FH-causing variant is identified, cascade testing is offered to at risk relatives. The pilot can screen and potentially detect multiple generations living with FH, reducing their risk of premature cardiovascular disease (CVD).

This is a new service which launched in 2021, and so there have been some unknowns and challenges for laboratories associated with CPSS samples, including:

• the infant blood samples received are significantly smaller (100ul) compared to those of routine peripheral blood samples (1-4ml). This smaller volume requires specialist extraction protocols and equipment.
• the reduced sample volume directly correlates to a reduced DNA yield. Thus, the assay used to analyse the patient’s DNA must be sensitive enough to produce accurate and reportable results from a lower starting amount of DNA. In house validation has proven that DNA extracted from these CPSS small volume samples, can be processed and reported alongside our routine screen samples.

A milestone moment – the first positive FH sample identified

The first CPSS sample was received into the North West GLH in May 2022 and to date we have processed 16 samples as part of this service. In November 2023, the laboratory identified the first FH-causing variant in a CPSS participant, and subsequent parental cascade testing has identified a relative with the same FH-causing variant who is thus at risk of premature CVD.

References:

[1] Data provided by the Familial Hypercholesterolaemia Service, Northern Genetics, August 2023

[2] Akioyamen et al (2017) PMID 28864697

[3] Wiegman et al (2015) PMID 26009596