Familial hypercholesterolemia (FH) is a common inherited disorder that results in premature atherosclerosis. Diagnosis of FH is suspected on the basis of clinical criteria, but confirmation requires genetic testing. In the era of statins, early diagnosis and initiation of treatment can modify disease progression and outcomes. Therefore, cascade screening with a combination of lipid concentration measurements and DNA testing should be used to identify relatives of index cases with a clinical diagnosis of FH. Autosomal dominant FH is related to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Genetic screening of the LDLR gene is challenging to achieve at a feasible cost, especially in people who do not have a founder effect. Nucleotide sequencing of all exons and flanking splicing regions in combination with multiplex ligation probe amplification to detect large insertions or deletions is considered the gold-standard approach to screen for LDLR mutations. Alternatively, the cDNA can be sequenced; however, this procedure is not suitable for use in large populations, because of the need of RNA extraction. Multiplex analysis can be appropriate for population with founder effects or a low number of different mutations. Finally, there are many techniques for a mutation scanning approach, which have some benefits over sequencing, and also with the potential for detecting known and novel mutations. Familial defective Apo B is amenable to genetic diagnosis by screening for a few mutations. Recently, gain-of-function mutations in PCSK9 gene have been demonstrated to cause FH phenotype. Strategies for population screening, cost-effectiveness of genetic screening, ethical aspects, and insurance policies are discussed and need implementation worldwide.
Keywords: cholesterol; familial defective Apo B; familial hypercholesterolemia; genetic screening; mutations.