Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia

Abstract

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. Nonpathogenicity of sequence changes may explain this phenomenon. To assess pathogenicity of a mutation we proposed three criteria:(1) mean LDL-C 4P75 in untreated mutation carriers; (2) higher mean LDL-C level in untreated carriers than in untreated noncarriers; and (3) higher percentage of medication users in carriers than in noncarriers at screening. We considered a mutation nonpathogenic 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 nonpathogenicity. Forty-six mutations had been tested in more than 50 untreated subjects, and three were nonpathogenic according to our criteria: one in LDLR (c.108C4A, exon 2) and two in APOB (c.13154T4C and c.13181T4C, both in exon 29). Segregation analysis also indicated nonpathogenicity. According to our criteria, three sequence variants were nonpathogenic. The criteria may help to identify nonpathogenic sequence changes in genetic cascade screening programs. Hum Mutat 31:752-760,

Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia

“…The medical history was recorded and physical examination performed according to a standardized procedure ( 13 ). Carotid arteries were examined with ultrasound to assess intima-media thickness (cIMT), using methodology previously described in detail ( 14 ).…”

Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia

“…12,13 Thus, carriers and unaffected relatives tested for confirmed nonpathogenic sequence variants were excluded, as were those who were tested for assumed pathogenic mutations with a low prevalence. 12,13 Step 3 was the selection of untreated individuals tested for a LDLR mutation only. Consequently, subjects tested for the pathogenic p.R3527Q mutation in APOB were excluded.…”

Microfluidic Amplification as a Tool for Massive Parallel Sequencing of the Familial Hypercholesterolemia Genes

“…One patient was heterozygous for 2 probable pathogenic mutations: 1 in the LDLR gene that was also reported in the LDLR database and 1 in the APOB gene. This novel APOB mutation was considered pathogenic on the basis of the phylogenetic comparison and the Grantham score; moreover, another mutation in the same codon of the gene was previously described in the literature (14). In the group of 71 new patients, 2 had a familial link to 2 other patients in this cohort.…”