Functionality of Sequence Variants in the Genes Coding for the Low-Density Lipoprotein Receptor and Apolipoprotein B in Individuals with Inherited Hypercholesterolemia

Roeland Huijgen (1) , Iris Kindt (2) , Sigrid W Fouchier (3) , Joep C Defesche (1) , Barbara A Hutten (4) , John Jp Kastelein (3) , Maud N Vissers (3)

1 Vascular Medicine
2 Foundation for the Identification of Persons with Inherited Hypercholesterolemia
3 Vascular Medicine
4 Clinical Epidemiology, Biostatistics and Bioinformatics

Objectives: Patients with familial hypercholesterolemia (FH) have elevated LDL-C levels, usually above the 90th percentile (P90) for age and gender. However, large scale genetic cascade screening for FH showed that 15% of the LDL-receptor (LDLR) or Apolipoprotein B (APOB) mutation carriers have LDL-C levels below P75. Non-pathogenicity of sequence changes may explain this phenomenon. Methods: To assess pathogenicity of a mutation we proposed three criteria: 1) mean LDL-C >P75 in untreated mutation carriers; 2) higher mean LDL-C level in untreated carriers than in untreated non-carriers; and 3) higher percentage of medication users in carriers than in non-carriers at screening. We considered a mutation non-pathogenic when none of the three criteria were met. We applied these criteria to mutations that had been determined in more than 50 untreated adults. Segregation analysis was performed to confirm non-pathogenicity. Results: Forty-six mutations had been tested in more than 50 untreated subjects and three were non-pathogenic according to our criteria: one in LDLR (c.108C>A, exon 2) and two in APOB (c.13154T>C and c.13181T>C, both in exon 29). Segregation analysis supported their non-pathogenic nature. Conclusions: According to our criteria, three sequence variants were non-pathogenic. The criteria may help to identify non-pathogenic sequence changes in genetic cascade screening programmes.

Mots clés: Life Sciences

Roeland Huijgen, Iris Kindt, Sigrid W Fouchier, Joep C Defesche, Barbara A Hutten, et al.. Functionality of Sequence Variants in the Genes Coding for the Low-Density Lipoprotein Receptor and Apolipoprotein B in Individuals with Inherited Hypercholesterolemia. Human Mutation, 2010, 31 (6), pp.752. ⟨10.1002/humu.21258⟩. ⟨hal-00552383⟩