Athar Mohammad, Toonsi Mawaddah, Abduljaleel Zainularifeen, Bouazzaoui Abdellatif, Bogari Neda M, Dannoun Anas, Al-Allaf Faisal A
Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
Science and Technology Unit, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
Life (Basel). 2023 Jul 11;13(7):1542. doi: 10.3390/life13071542.
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.
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.
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.
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.
家族性高胆固醇血症（FH）是一种遗传性疾病，可导致一个人一生中血液胆固醇升高。如果不进行治疗，FH可导致心肌梗死甚至猝死。FH被认为主要由低密度脂蛋白受体（LDLR）基因的变异引起。本研究旨在调查FH患者的基因变异，验证其致病性，并了解基因型与表型之间的关系。此外，回顾性研究评估了LDLR无效变异与降脂治疗反应之间的关系。
本研究利用高通量下一代测序对FH相关基因进行基因筛查，并利用毛细管测序进行级联筛查。此外，采用生物信息学分析来描述所揭示的新变异对相应RNA分子结构特征的致病作用。
我们研究了一个患有三代FH的沙特家族中高胆固醇血症的临床症状。我们在LDLR中发现了一个新的移码变异（c.666_670dup，p.(Asp224Alafs*43)）和APOB基因中一个已知的单核苷酸变异（c.9835A>G，p.(Ser3279Gly)）。据认为，LDLR变异导致蛋白质过早截断，可能是通过无义介导的蛋白质降解。根据美国医学遗传学与基因组学学会（ACMG）指南，LDLR变异被强烈预测为致病性变异，并与该家族的FH临床特征共分离。这种LDLR变异表现出严重的临床FH表型，并且局限于LDLR蛋白的配体结合域。根据计算功能表征，这种LDLR变异预计会改变RNA分子的自由能动态，从而影响其稳定性。这种移码变异被认为会消除LDLR中受体循环和LDL颗粒结合所需的重要功能域。我们深入了解了LDLR基因存在无效变异的FH患者对降脂治疗的反应。
这些发现扩展了FH变异的范围，并通过改善FH患者的诊断、理解基因型-表型关系、预后和个性化治疗，有助于冠状动脉疾病的预防工作。
