Children with hypercholesterolemia of unknown cause: Value of genetic risk scores.

Background: Familial hypercholesterolemia (FH) is caused by mutations in LDLR, APOB, or PCSK9, and in a previous study, we identified a causative mutation in these FH genes in 95% (255 of 269) of children with the FH phenotype. It has been hypothesized that a polygenic form of hypercholesterolemia is present in FH patients in whom no mutation is identified in the 3 FH genes.

Objective: To address whether a polygenic form of hypercholesterolemia, defined as high-weighted effect of low-density lipoprotein cholesterol (LDL-C) raising SNPs expressed as the genetic risk score (GRS), is present in the remaining 14 children.

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.

Exome sequencing in suspected monogenic dyslipidemias.

Background: Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias.

Methods And Results: We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol.

Current novel-gene-finding strategy for autosomal-dominant hypercholesterolaemia needs refinement.

Aims: Autosomal-dominant hypercholesterolaemia (ADH) is a heterogeneous common disorder, and uncovering the molecular determinants that underlie ADH is a major focus of cardiovascular research. However, despite rapid technical advances, efforts to identify novel ADH genes have yet not been very successful and are largely challenged by phenotypic and genetic heterogeneity of this disease. We aimed to investigate the impact of this phenotypic heterogeneity on successfully finding new genes that are involved in ADH.