Genetic heterogeneity of autosomal dominant hypercholesterolemia

Abstract

Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated elevation of plasmatic low-density lipoprotein cholesterol associated with high risk of premature cardiovascular complications. More than 1000 mutations in the LDLR gene and 9 in the APOB gene have been implicated. We have shown further heterogeneity with the discovery of missense mutations in the PCSK9 gene resulting in ADH. Different studies have tried to evaluate the respective contribution of mutations in each gene to the disease, but results were not always in agreement. After a brief overview of mutations reported for each gene, strategies and results of these different studies are reviewed and analyzed. Altogether, numerous reports give evidence for the existence of a greater level of genetic heterogeneity in ADH and the involvement of still unknown genes.

A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1

“…Overall, the best estimated proportion of individuals without a mutation in any of the three identified ADH genes is 15.25%. 36 This group of new forms of ADH is very probably itself heterogeneous, and the proportion of HCHOLA4-affected individuals may not be more important than that of PCSK9 carriers that we estimated at 1.5%. 36 HCHOLA4-linked ADH may thus be considered as a very rare form of ADH.…”

“…The existence of a greater level of genetic heterogeneity is in agreement with recent reports as the proportion of ADH subjects without an identified mutation ranges from 12 to 72% depending on the study. 36 Such a large difference in mutation identification is probably due to different sample sizes, heterogeneous clinical definitions, and screening protocols. Overall, the best estimated proportion of individuals without a mutation in any of the three identified ADH genes is 15.25%.…”

The Role of Genetic Counselors for Patients with Familial Hypercholesterolemia

“…There is evidence that null mutations in LDLR are associated with a more severe phenotype [11,12]. It has been estimated that mutations in APOB account for approximately 5.5 % of FH cases, while mutations in PCSK9 account for approximately 1.5 % [10].…”

“…LDLR genetic testing has been shown to identify 70-80 % of individuals with a ''definite'' FH clinical diagnosis and 20-30 % with a less certain diagnosis [6]. Over 1,000 mutations in LDLR have been identified in FH patients [10]. There is evidence that null mutations in LDLR are associated with a more severe phenotype [11,12].…”

Familial Hypercholesterolemia: A Decade of Progress

“…The second most common group are defects in the formation of apolipoprotein B, the major protein on LDL, so that binding of the protein to the receptor is impaired. 3 Finally, genes related to the regulation of LDL receptor function have recently been uncovered, PCSK9 is important in this process, and defects that impair receptor function increase LDL levels and risk for heart disease while those that enhance LDL receptor function lower the risk for heart disease. 4 In Europe, genotyping of patients suspected of having FH is common and a genetic defect is identified at least 80% of the time.…”