Physicians' Academy for Cardiovascular Education

Genetic testing for autosomal dominant hypercholesterolemia in Norwegian patients and relatives

Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020

Literature - Leren TP and Bogsrud MP. - Atherosclerosis. 2021;322:61-66. doi: 10.1016/j.atherosclerosis.2021.02.022.

Introduction and methods

The prevalence of heterozygous familial hypercholesterolemia (FH) is 1/200-1/500 in most Western countries [1,2]. In Norway, a prevalence of 1/313 has been estimated [3].

Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the LDLR, APOB, and PCSK9 genes. More than 2300 different loss-of-function mutations in the LDLR gene have been reported that result in FH [4-6]. A few missense mutations have been reported in the APOB gene and cause familial defective apolipoprotein B-100 (FDB) [3,7]. And a few gain-of-function mutations have been found in the PCSK9 gene that are causal of FH3 [8].

Patients with ADH have a high risk of coronary heart disease (CHD) [9,10]. To reduce the risk of CHD, identification and treatment at an early age of these patients is therefore necessary [11]. This study presents the data of diagnostic screening for mutations in LDLR, APOB, and PCSK9 genes in unrelated hypercholesterolemia patients and their family members from Norway.

Genetic testing for ADH was performed in 29,449 unrelated adult index patients with a total serum cholesterol of at least 6 mmol/L from 1993 to 2020. In addition, 14,230 relatives were screened. Molecular testing was done at Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital, Norway. Sanger sequencing of the LDLR gene (NM_000527.4) with at least 20 bp flanking intronic region was done. For the APOB gene (NM_000384.3), a 101 bp fragment spanning nucleotides c.10537-c.10637 in exon 26 was sequenced. This exon contains codon 3527, which is the only codon where mutations are definitely causal of FDB [12,13]. PCSK9 gene (NM_174936.4) with flanking introns was sequenced and in addition multiplex ligation-dependent probe amplification (MLPA) analysis of the LDLR gene was performed in those with total serum cholesterol of ≥8 mmol/L without an underlying mutation in the LDLR gene or APOB exon 26. The mean age at the time of genetic testing of index patients was 47.4 ± 18.2 (SD) years and 36.3 ± 18.3 (SD) years of relatives.

Main results


This study presented the status of molecular genetic testing for hypercholesterolemia in Norway from 1993 to 2020. Heterozygous mutations in the LDLR gene were most prevalent in patients with ADH.


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