A large German screening program has demonstrated the feasibility of identifying FH through childhood LDL-C testing and genetic sequencing, while Spanish data show the benefits of early treatment.
Early identification and treatment of familial hypercholesterolaemia (FH) could substantially reduce the lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C) and the risk of premature cardiovascular disease, according to findings from two large European studies.
Research from Spain has shown that children and adolescents with genetically confirmed FH who began cholesterol-lowering medication during childhood had a substantially lower cumulative LDL-C burden by early adulthood than affected parents who started treatment much later in life, as well as markedly fewer cardiovascular events during follow-up.
The SAFEHEART study was a multicentre prospective cohort of 348 children under 18 years with genetically confirmed heterozygous FH, 165 unaffected relatives (also under 18), and 288 parents with FH. Participants were recruited between 2004 and 2020 and were followed up until the end of 2024 (median follow-up 12.4 years). They received routine clinical care from their treating physicians according to the guidelines applicable at the time.
FH-confirmed children initiated cholesterol-lowering medication (CLM) at a median age of 14.5 years, compared with 36.1 years among FH parents. Median untreated LDL-C at enrolment was 5.46mmol/L among FH children, 2.63mmol/L among unaffected children, and 7.19mmol/L among FH parents.
By the end of follow-up, FH children receiving CLM had a median LDL-C of 3.00mmol/L – an absolute reduction of 2.60mmol/L, or 47.4% from their untreated levels, bringing levels closer to those seen in unaffected children.
FH parents had a lower median LDL-C at the end of follow-up (2.44mmol/L) but their larger reduction reflected their substantially higher untreated levels, authors noted.
The most striking difference between the generations emerged when researchers looked at cumulative LDL-C exposure over time. Rather than considering cholesterol levels at a single point, the investigators calculated the LDL-C burden over a person’s lifetime, reflecting both how high LDL-C had been and how long the individual had been exposed to it.
Among 106 FH children who had been followed up into their 30s, median LDL-C was 3.01mmol/L, while the 59 FH parents with measurements available by age 40 had LDL-C of 4.50mmol/L.
By this point, the median cumulative LDL-C burden was 5909.0mg/dL-years among the FH children, compared with 10,206.8mg/dL-years among their FH parents – a substantially lower lifetime LDL-C exposure associated with starting treatment earlier.
The difference was also reflected in cardiovascular outcomes. During follow-up, one FH child (0.3%) experienced a cardiovascular event, compared with no events among the unaffected children and 34 events (11.8%) among FH parents. The event in the FH group was a non-fatal acute coronary syndrome at age 25.2 years in a participant who had never smoked, was receiving CLM, and had a Lp(a) level of 110mg/dL at inclusion. The earliest cardiovascular event among FH parents occurred at 31.1 years of age.
Cardiovascular events were considerably more common among men: 21.2% of male FH parents experienced an event compared with 2.1% of female parents, while six FH parents (all male) died from cardiovascular causes during follow-up and five had previously experienced a non-fatal cardiovascular event.
When cardiovascular events that had occurred before enrolment were also included, 0.3% of FH children and 18.4% of FH parents had experienced a first cardiovascular event, including 32.2% of male FH parents and 4.2% of female parents.
By age 39, cardiovascular events had occurred in 0.3% of FH children, compared with 5.2% of FH parents and none of the unaffected children. None of the FH children had established cardiovascular disease when they entered the study, compared with 32 FH parents (11.1%), most of whom had coronary artery disease.
The findings were consistent with the underlying concept that cardiovascular risk from LDL-C depends not only on how high cholesterol is, but also on how long the arteries are exposed to it, the researchers explained.
“The effect of high LDL-C on cardiovascular risk depends on both the magnitude and duration of the exposure, that is, the cumulative cholesterol burden,” authors wrote.
“In FH, patients have high LDL-C life-long if left untreated (or not optimally treated), resulting in an elevated risk of premature ASCVD. Therefore, prevention of atherosclerosis in FH should optimally start in childhood to overcome the impact of the cumulative burden of LDL-C over time, potentially reducing cardiovascular risk to that in the general population without FH.
“Our study strongly supports and provides new data on the impact of moving the focus of FH identification from adulthood to childhood.”
At the same time, the VRONI screening program in Bavaria, Germany, demonstrated the feasibility of a two-step approach which could identify FH in children through routine care.
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The program began in September 2020 and involved around 480 paediatricians by October 2024, representing approximately 36% of practising paediatricians in the region. They were invited to offer FH screening to all children aged 5–15 years during routine examinations, requiring only a 0.2mL blood sample from a fingertip without fasting requirements, which was then sent to the German Heart Centre Munich for LDL-C measurement.
Children with an LDL-C concentration of at least 3.36mmol/L were then offered genetic testing from the same fingertip blood sample. This threshold was roughly the 93rd percentile in the screened population, corresponding to both the defined concentration for hypercholesterolaemia in this age group and the LDL-C level at which statin treatment could be considered in children with genetically confirmed FH.
The children with hypercholesterolaemia then underwent venous blood collection for a more extensive lipid profile, including total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglycerides, and Lp(a). Information on weight, height, waist circumference, number of siblings, parental birth years, and family history of hypercholesterolaemia or premature cardiovascular disease was also collected.
Over the four years, 25,431 children were enrolled in the program (51.6% male, median age at enrolment 9.1 years, median LDL-C concentrations 2.28mmol/L [range 0.29-8.46mmol/L]).
The LDL-C threshold was exceeded by 1689 children (6.6% of the cohort, median age 9.8 years), 1670 of whom underwent genetic testing. FH-causing variants were detected in 283 children, meaning 17% of genetically tested children with LDL-C above the screening threshold had an FH-causing variant (1.1% of the overall cohort).
The likelihood of identifying FH rose sharply as LDL-C increased. Among children with LDL-C of 3.36–3.49mmol/L, 4.7% carried an FH-causing variant. This increased to 78.6% among those with LDL-C above 5.17mmol/L.
All identified genetic findings were confirmed using a second independent sample, and all affected children were heterozygous carriers.
The researchers also noted a 10-fold higher diagnostic yield in children than in adults. Among adults with LDL-C above the 93rd percentile (≥4.92mmol/L) only 1.7% (24/1386) carried an FH-causing variant, compared to the 17% prevalence among children exceeding the 93rd percentile.
The researchers initially estimated FH prevalence at 1 in 90, but this was partly driven by a founder LDLR variant identified in 63 children that was approximately 40 times more common than the European average.
After adjustment for ascertainment bias (paediatricians who recruited fewer children tended to identify a higher proportion with monogenic FH, suggesting some practices were preferentially screening children in whom FH was already suspected), the predicted prevalence was 1 in 163 (0.61%), which was highly consistent with estimates from large genomic datasets such as gnomAD, which found a prevalence of approximately 1 in 165 among 622,057 people, and the UK Biobank, which found around 1 in 176 among 48,741 people.
The program also found that next-generation sequencing had a 78% higher diagnostic yield than the targeted genetic panel. A focused panel covering the 48 most common FH-causing variants identified 157 cases, while next-generation sequencing identified 283 – an additional 126 cases.
The increasing sensitivity and affordability of next-generation sequencing may make wider implementation more feasible, the authors noted.
There is no universal approach to identifying FH early, despite it being recommended by organisations such as the European Atherosclerosis Society, National Lipid Association, and American Academy of Pediatrics. It was also identified as a priority by the European Union in its 2021 call for a public health genomics approach to improve the early detection of rare and genetic diseases but currently, only Slovenia and Slovakia have established national programs.
In many countries, children are often only tested opportunistically, such as after a cardiovascular event, discovery of high cholesterol in a family, or through cascade screening after an FH-causing variant has been found in a relative. However, detection rates vary considerably between countries depending on the availability and quality of cascade screening programs.
Together, the findings support treating FH as a paediatric cardiovascular prevention condition, rather than waiting until adulthood or until cardiovascular disease has already developed.
European Heart Journal, 15 June 2026 (SAFEHEART)
