BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. METHODS: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. RESULTS: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10-16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10-16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). CONCLUSIONS: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.

1st Department of Pediatrics National and Kapodistrian University of Athens and Department of Inborn Errors of Metabolism and Inherited Dyslipidemias MITERA Children's Hospital Athens Greece

1st Department of Pediatrics National and Kapodistrian University of Athens Greece

3rd Department of Internal Medicine General University Hospital and 1st Faculty of Medicine Charles University U Nemocnice 1 Prague 2 128 08 Czech Republic

Cardiovascular Research Group Research and Development Unit Department of Health Promotion and Chronic Diseases National Institute of Health Doutor Ricardo Jorge Lisbon Portugal and University of Lisboa Faculty of Sciences BioISI Biosystems and Integrative Sciences Institute Lisboa Portugal

Centre de Génétique Humaine UCL Cliniques Universitaires Saint Luc Bruxelles Belgium

Centre for Cardiovascular Genetics Institute for Cardiovascular Science University College London London United Kingdom

Centre for Cardiovascular Surgery and Transplantation Czech Republic and Medical Faculty Masaryk University Pekarska 53 656 91 Brno Brno Czech Republic

Centre for Heart Muscle Disease Institute for Cardiovascular Science University College London London United Kingdom

Centre of Molecular Biology and Gene Therapy University Hospital Brno Brno Czech Republic

Centres Hospitaliers Jolimont Lipid Clinic Haine Saint Paul Belgium

Department of Laboratory Medicine Medical University of Vienna Vienna Austria

Department of Nutrition University of Oslo Oslo Norway

Department of Pediatrics Amsterdam University Medical Centers Amsterdam the Netherlands

Departments of Cardiology and Internal Medicine Erasmus Medical Center Rotterdam the Netherlands

Division of Pediatric Pulmonology Allergology and Endocrinology Department of Pediatrics and Adolescent Medicine Comprehensive Center Pediatrics Medical University Vienna Austria

Institute of Genetic Epidemiology Department of Genetics and Pharmacology Medical University of Innsbruck Schöpfstraße 41 6020 Innsbruck Austria

Lysosomal Disorders Unit Royal Free Hospital London United Kingdom

National Advisory Unit on Familial Hypercholesterolemia Department of Endocrinology Morbid Obesity and Preventive Medicine Oslo University Hospital Oslo Norway

Unit for Cardiac and Cardiovascular Genetics Department of Medical Genetics Oslo University Hospital Oslo Norway