Among 269 children with an unequivocal autosomal dominant hypercholesterolemia phenotype, a causative mutation was identified in 95% (LDLR 95%, APOB 5%).
Observational (n=269)
In a rigorously selected pediatric cohort with an unequivocal ADH phenotype, 95% of cases had an identifiable causative mutation in known genes (LDLR or APOB), suggesting most large-effect genes for ADH are already known.
BACKGROUND: Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. Mutations in the genes encoding for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) underlie ADH. Nevertheless, a proportion of individuals who exhibit the ADH phenotype do not carry mutations in any of these 3 genes. Estimates of the percentage of such cases among the ADH phenotype vary widely. We therefore investigated a large pediatric population with an unequivocal ADH phenotype to assess the molecular basis of hereditary hypercholesterolemia and to define the percentage of individuals with unexplained dyslipidemia. METHODS AND RESULTS: We enrolled individuals with low-density lipoprotein cholesterol levels above the 95th percentile for age and gender and an autosomal dominant inheritance pattern of hypercholesterolemia from a large referred pediatric cohort of 1430 children. We excluded children with thyroid dysfunction, nephrotic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, and obesity (body mass index >75th percentile for age and gender), as well as children referred via a cascade screening program and those from families with a known molecular diagnosis. Of the 269 children who remained after the exclusion criteria were applied, 255 (95%) carried a functional mutation (LDLR, 95%; APOB, 5%). CONCLUSION: In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date.
Graaf et al. (Tue,) conducted a observational in Autosomal dominant hypercholesterolemia (n=269). Genetic screening for LDLR, APOB, and PCSK9 mutations was evaluated on Presence of a functional mutation. Among 269 children with an unequivocal autosomal dominant hypercholesterolemia phenotype, a causative mutation was identified in 95% (LDLR 95%, APOB 5%).
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