Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship

Background —Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease (ASCVD). HoFH is caused by mutations in several genes, including LDL receptor ( LDLR ), apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and LDL protein receptor adaptor 1 ( LDLRAP1 ). No epidemiological studies have assessed HoFH prevalence, or the clinical and molecular characteristics of this condition. Here we aimed to characterize HoFH in Spain. Methods and Results —Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for FH in Spain between 1996 and 2015 (n=16,751). Clinical data included baseline lipid levels and ASCVD events. A total of 97 subjects were identified as having HoFH-of whom, 47 were true homozygous (1 for APOB , 5 for LDLRAP1 , and 41 for LDLR ), 45 compound heterozygous for LDLR , 3 double heterozygous for LDLR and PSCK9 , and 2 double heterozygous for LDLR and APOB . No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450,000. Compared to compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more ASCVD events. Conclusions —HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve FH diagnosis accuracy.