Double heterozygous familial hypercholesterolaemia: Case series, genetics and Cascade screening of families

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism characterized by high levels of LDL-cholesterol (LDL-C) in the blood. Studies identified more than 1,000 mutations of the LDLR gene in FH patients with incidence rates between 1: 500 and 1: 300. The mutation that occurs primarily in: LDLR, apoB, PCSK9, LDLRAP1 genes, 80% of which were detected the LDLR gene mutation. Nowaday, FH disease has not been paid much attention, leading to a delay in treatment. Objectives: identify mutations in other family members of the patient FH. Subjects and Methods: 14 family members of FH patients were gene analyzed, identified mutations on exons 4, 9 LDLR genes. Results: 11/15 family members carrying heterozygous mutations on exon 4 and exon 9 of LDLR gene. Patient and 1 family member detected and treated late, leading to complications of myocardial infarction. Conclusion: Therefore, Cascade screening of patient's family members has an important role in early detection, genetic counseling and treatment, even in cases where pedigree members do not have xanthomas and no increase or slight increase in blood lipids. This is the basis for early counseling and treatment for members with mutations, reducing the risk of coronary artery diseases in the future.

Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes

Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, characterized by increased levels of total and LDL plasma cholesterol, which leads to premature atherosclerosis and coronary heart disease. FH phenotype has considerable genetic heterogeneity and phenotypic variability, depending on LDL receptor activity and lifestyle. To improve diagnosis and patient management, here, we characterized two single nucleotide missense substitutions at Methionine 1 of the human LDLR gene (c.1A>T/p.(Met1Leu) and c.1A>C/p.(Met1Leu)). We used a combination of Western blot, flow cytometry, and luciferase assays to determine the effects of both variants on the expression, activity, and synthesis of LDLR. Our data show that both variants can mediate translation initiation, although the expression of variant c.1A>T is very low. Both variants are in the translation initiation codon and codify for the same amino acid p.(Met1Leu), yet they lead to different levels of impairment on LDLR expression and activity, corroborating different efficiencies of the translation initiation at these non-canonical initiation codons. The functional data of these variants allowed for an improved American College of Medical Genetics (ACMG) classification for both variants, which can allow a more personalized choice of the lipid-lowering treatment and dyslipidemia management, ultimately improving patients’ prognosis.

Genetics of severe hypercholesterolemia in the general population: Insights from the STANISLAS cohort

Background: Severe hypercholesterolemia (SH) is a common condition characterized by increased levels of total and low-density lipoprotein cholesterol (LDLc). Methods: The aim of this study is to screen for prevalence of hypercholesterolemia, perform heritability estimation of circulating lipoproteins and study the association between SH cases and surrogate cardiovascular disease markers among participants of STANISLAS cohort. Gene candidate analyses were utilized to investigate the association between lipid levels, SH and polymorphisms from the three commonly reported genes (APOB, LDLR and PCSK9). Results: Participants with SH (n=102; 6.9%) were older (58 vs. 51yr), had higher total cholesterol (290 vs. 209mg/dL), LDLc (206 vs. 136mg/dL) and triglycerides (114 vs. 88 mg/dL). Despite smoking less, they had carotid plaques more frequently (21.2 vs. 9.3%), higher cIMT (676 vs. 597µm), and had more frequent family history cardiovascular disease. The circulating lipid levels have an important heritability: LDLc 51.6%, HDLc 66.6%, total cholesterol 49.8%, and triglycerides 41.4%. The SNPs located in LDLR gene present the strongest association with LDLc levels: rs55997232, rs17242395, rs1010679, and rs11668477. Conclusion: In a healthy cohort, participants with SH had premature vascular damage. LDLc had an important component of heritability and SNPs linked to the LDLR gene presented a strong association with LDLc. These findings reinforce the need for an early identification and treatment of SH subjects, which is mostly polygenic.

Familial Hypercholesterolemia and Cerebral Infarction - A Case Report

Background: Familial hypercholesterolemia has various presentations mostly including early-onset cardiovascular diseases, remarkable skin and tendon xanthomas. By comparison, Cerebral Infarction due to familial hypercholesterolemia is extremely rare. Case presentation: We present a 41-year-old man who was admitted to our hospital with dizziness, vertigo, slurred speech, weakness in his left limbs. He had family history of Hyperlipidemia in older sister . Head CT scan demonstrated multiple acute cerebral infarction in the right frontal and parietal lobes, and arterial plaques was found in the bifurcation of common carotid artery. The severe carotid stenosis was located in the initial segment of the right internal carotid artery. Histopathologic findings were consistent with xanthoma. Especially, molecular analysis of the LDLR gene was made, which identified heterozygous missense mutation in exon 12 of the LDLR gene. The final diagnosis of cerebral infarction associated with familial hypercholesterolemia was made. The patient was referred to a nutritionist for dietary advice, and was treated with Tab. Finally, the patient recovered well. The symptoms of brain infarct vanished and no recurrence occurred during follow-up.Conclusions: In the present case, the acute cerebral infarction is most likely due to hypercholesterolemia, as his family history of hypercholesterolemia, and arterial plaques and severe carotid stenosis was found by CTA. This case highlights the importance of the early diagnosis and treatment of hypercholesterolemia, which may help in preventing the development of cardiovascular and cerebrovascular diseases.

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania

This study identifies the genetic background of familial hypercholesterolemia (FH) patients in Romania and evaluates the association between mutations and cardiovascular events. We performed a prospective observational study of 61 patients with a clinical diagnosis of FH selected based on Dutch Lipid Clinic Network (DLCN) and Simon Broome score between 2017 and 2020. Two techniques were used to identify mutations: multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. The mutation rate was 37.7%, i.e., 23 patients with mutations were identified, of which 7 subjects had pathogenic mutations and 16 had polymorphisms. Moreover, 10 variants of the low-density lipoprotein receptor (LDLR) gene were identified in 22 patients, i.e., one variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in six patients, and one variant of the apolipoprotein B (APOB) gene in three patients. Of the LDLR gene variants, four were LDLR pathogenic mutations (c.81C > G, c.502G > A, c.1618G > A mutations in exon 2, exon 4, exon 11, and exon 13–15 duplication). The PCSK9 and APOB gene variants were benign mutations. The pathogenic LDLR mutations were significant predictors of the new cardiovascular events, and the time interval for new cardiovascular events occurrence was significantly decreased, compared to FH patients without mutations. In total, 12 variants were identified, with four pathogenic variants identified in the LDLR gene, whereas 62.3% of the study population displayed no pathological mutations.