Key result
A novel pathogenic frameshift variant in the LDLR gene (c.666_670dup) was identified in a Saudi family with three generations of severe familial hypercholesterolemia.
Why the study?
This study aimed to investigate genetic variants in patients with familial hypercholesterolemia, verify their pathogenicity, comprehend genotype-phenotype relationships, and assess the relationship between LDLR null variants and response to lipid-lowering therapy.
Observational
Identification of a novel pathogenic LDLR frameshift variant expands the genetic spectrum of familial hypercholesterolemia and may aid in diagnosis and personalized therapy.
Supports expanded LDLR variant analysis in FH; leaves open prospective validation of pathogenicity and genotype-phenotype links.
BACKGROUND: Familial Hypercholesterolemia (FH) is a hereditary condition that causes a rise in blood cholesterol throughout a person's life. FH can result in myocardial infarction and even sudden death if not treated. FH is thought to be caused mainly by variants in the gene for the low-density lipoprotein receptor (LDLR). This study aimed to investigate the genetic variants in FH patients, verify their pathogenicity, and comprehend the relationships between genotype and phenotype. Also, review studies assessed the relationship between the LDLR null variants and the reaction to lipid-lowering therapy. METHODS: The study utilised high-throughput next-generation sequencing for genetic screening of FH-associated genes and capillary sequencing for cascade screening. Furthermore, bioinformatic analysis was employed to describe the pathogenic effects of the revealed novel variant on the structural features of the corresponding RNA molecule. RESULTS: We studied the clinical signs of hypercholesterolemia in a Saudi family with three generations of FH. We discovered a novel frameshift variant (c.666_670dup, p.(Asp224Alafs*43) in the LDLR and a known single nucleotide variant (c.9835A > G, p.(Ser3279Gly) in the APOB gene. It is thought that the LDLR variant causes a protein to be prematurely truncated, likely through nonsense-mediated protein decay. The LDLR variant is strongly predicted to be pathogenic in accordance with ACMG guidelines and co-segregated with the FH clinical characteristics of the family. This LDLR variant exhibited severe clinical FH phenotypes and was restricted to the LDLR protein's ligand-binding domain. According to computational functional characterization, this LDLR variant was predicted to change the free energy dynamics of the RNA molecule, thereby affecting its stability. This frameshift variant is thought to eliminate important functional domains in LDLR that are required for receptor recycling and LDL particle binding. We provide insight into how FH patients with a null variant in the LDLR gene respond to lipid-lowering therapy. CONCLUSIONS: The findings expand the range of FH variants and assist coronary artery disease preventive efforts by improving diagnosis, understanding the genotype-phenotype relationship, prognosis, and personalised therapy for patients with FH.
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Athar et al. (2023) conducted an observational in Familial Hypercholesterolemia. LDLR frameshift variant (c.666_670dup) was evaluated on Identification and characterization of genetic variants. A novel pathogenic frameshift variant in the LDLR gene (c.666_670dup) was identified in a Saudi family with three generations of severe familial hypercholesterolemia.
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