Aims Autosomal-dominant hypercholesterolaemia (ADH) is a heterogeneous common disorder, and uncovering the molecular determinants that underlie ADH is a major focus of cardiovascular research. However, despite rapid technical advances, efforts to identify novel ADH genes have yet not been very successful and are largely challenged by phenotypic and genetic heterogeneity of this disease. We aimed to investigate the impact of this phenotypic heterogeneity on successfully finding new genes that are involved in ADH.

Methods and results For the ADH phenotype, subjects are considered as affected according to plasma cholesterol levels above the 95th percentile for age and gender. The disease penetrance is generally set at 0.9. These parameters were evaluated in 10 000 carriers of true pathogenic APOB and LDLR mutations and 20 000 relatives negative for the familial mutations. Application of the above parameters in almost a thousand families included in this study would have identified the causal variant in only 38% of all families. An average penetrance of 0.9 or higher, with a cut-point at the 95th percentile, was only observed for LDLR nonsense mutations. For APOB and LDLR missense mutations, a disease penetrance of 0.9 or higher is only expected, when total cholesterol and low-density lipoprotein cholesterol cut-points between the 75th and 90th percentile are used to determine an individual's disease status.

Conclusions Although pathogenic LDLR and APOB mutations do follow Mendelian patterns of inheritance, the extensive variation in genotype and phenotype for well-known ADH-causing mutations emphasises that current criteria and strategies indeed are likely to hamper the identification of novel genes related to ADH. These findings provide a basis for the revision of our assessment on who is affected and who is not and emphasise the essence of pedigree information and mapping data before exome sequencing is applied in order to increase success rates of finding new genes related to ADH.