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Published on: September 15, 2018
Novel LDLR Variant in Familial Hypercholesterolemia: NGS-Based Identification, In Silico Characterization, and
Mohammad Athar1,2, Mawaddah Toonsi3, Zainularifeen Abduljaleel1,2
1Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
Insights
This study identified a novel LDLR gene variant in a Saudi family with Familial Hypercholesterolemia (FH), improving FH diagnosis and personalized treatment strategies. The findings enhance understanding of genotype-phenotype correlations for FH patients.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Biochemistry
Background:
- Familial Hypercholesterolemia (FH) is an inherited condition causing elevated cholesterol, increasing heart attack risk.
- Genetic variants, particularly in the low-density lipoprotein receptor (LDLR) gene, are primary causes of FH.
- Early diagnosis and treatment are crucial to prevent severe cardiovascular events.
Purpose of the Study:
- To investigate genetic variants in FH patients and their pathogenicity.
- To understand the genotype-phenotype relationship in FH.
- To review the response of LDLR null variant patients to lipid-lowering therapy.
Main Methods:
- High-throughput next-generation sequencing for genetic screening.
- Capillary sequencing for cascade screening.
- Bioinformatic analysis to assess variant pathogenicity and RNA structural effects.
Main Results:
- A novel LDLR frameshift variant (c.666_670dup, p.(Asp224Alafs*43)) and a known APOB variant (c.9835A > G, p.(Ser3279Gly)) were identified in a Saudi FH family.
- The novel LDLR variant is predicted to be pathogenic, causing premature protein truncation and affecting LDL binding and receptor recycling.
- The variant co-segregated with severe FH phenotypes within the family.
Conclusions:
- The identified FH variants expand the known spectrum of genetic causes for the condition.
- Improved understanding of genotype-phenotype correlations aids in diagnosis and prognosis.
- Findings support personalized therapy approaches for FH patients, potentially improving cardiovascular disease prevention.
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.
