Submission Details

Familial hypercholesterolemia (FH) is an inborn error of lipid metabolism that leads to deficiency or disrupted internalization of the low density lipoprotein receptor (LDLR), elevated serum low density lipoprotein (LDL) cholesterol levels, and subsequent increased risk for coronary artery disease and other complications.

From 1976-1986 multiple studies implicated a causative role for LDLR in familial hypercholesterolemia, including at the protein level (PMID: 189940) and finally at the genome level (e.g. PMIDs:3924410, 3549308).

Monoallelic variation in the LDLR gene is associated with 2-3 fold increased plasma LDL levels with typical onset around the third decade of life, whereas biallelic variation is associated with 6-8 fold increased plasma LDL with onset as early as childhood and coronary artery disease by the second decade of life or earlier (PMID: 24404629/BookshelfID: NBK174884). Xanthomas can also be observed in individuals with biallelic LDLR variants.

Familial hypercholesterolemia due to genetic variation in the LDLR gene therefore follows a dosage dependent pattern, consistent with semidominant inheritance, in which the presence of biallelic variants results in an earlier onset, more severe phenotype than individuals with a monoallelic variant.

As such, a semidominant mode of inheritance was chosen and this curation includes evidence from individuals reported to have autosomal dominant and recessive inheritance. Thousands of variants in LDLR have been described including nonsense, missense, frameshift, large and small deletions, duplications, and more, per ClinVar and LOVD databases. Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 40 years, therefore a significant amount of case-level data, segregation data, and experimental data is available and the maximum score for genetic evidence (12 points) and experimental evidence (6 points) has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. The mechanism of pathogenicity for this gene-disease relationship is loss of function, in which the receptor is not able to effectively bind and/or internalize plasma LDL for degradation, thus resulting in increased levels of LDL in the arteries (PMID:189940). This gene-disease association is also supported by animal models, biochemical studies, protein interaction, in vitro functional assays, and rescue assays (PMIDS:2280177, 8349823, 17080197). In summary, LDLR is definitively associated with familial hypercholesterolemia in a semidominant inheritance pattern. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease relationship was approved on Feb 24, 2021 by the General Gene Curation Expert Panel.