Sequencing for LIPA mutations in patients with a clinical diagnosis of familial hypercholesterolemia.

BACKGROUND AND AIMS: We recently identified lysosomal acid lipase (LAL) deficiency, a recessive disease caused by mutations in LIPA, in 3 patients with a clinical diagnosis of familial hypercholesterolemia (FH). We aimed to determine the prevalence of LIPA mutations among individuals with a clinical FH diagnosis. METHODS: In 276 patients with phenotypic FH, in whom no genetic basis for their phenotype was found, LIPA was sequenced. All variants were assessed for pathogenicity using a literature search and in silico prediction models. RESULTS: We included 213 adults and 63 children with mean (±SD) LDL-C levels of 7.8 ± 1.3 and 4.4 ± 1.5 mmol/L, respectively. Twenty-one variants were identified. Six patients were heterozygous carrier of a (potentially) pathogenic mutation. No homozygous LIPA mutation carriers were identified. CONCLUSIONS: Our data show that LAL deficiency was not missed as diagnosis in our study population but the frequency of heterozygous LIPA mutations implies that the FH population might be relatively enriched with LIPA mutation carriers.

Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels.

Autosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL-cholesterol (LDL-C) levels below the 50th percentile for age and gender prior to lipid-lowering therapy. The genes encoding APOB, PCSK9, and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss-of-function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in five (6.7%) probands, reducing LDL-C by 56%. Rare variants in PCSK9, and ANGPTL3 completely correcting the hypercholesterolemic phenotype were not found. The common variants p.N902N, c.3842+82T>A, p.D2312D, and p.E4181K in APOB, and c.1863+94A>G in PCSK9 were significantly more prevalent in our cohort compared to the general European population. Interestingly, 40% of our probands carried at least one minor allele for all four common APOB variants compared to 1.5% in the general European population. While we found a low prevalence of rare variants in our cohort, our data suggest that regions in proximity of the analyzed loci, and linked to specific common haplotypes, might harbor additional variants that correct an ADH phenotype.