OBJECTIVE: To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestations and gene variation. METHODS: Two patients (patient 1 and 2) with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects. A retrospective study method was used to collect clinical and family history data of the two patients. And 2 mL of peripheral venous blood from each of the two patients was collected, and genomic DNA extraction was performed on the blood samples. Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing (WES). Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the "ACMG Guidelines"), and the impact of variant was analyzed using multiple bioinformatics tools including SIFT, PolyPhen-2, and SWISS-MODEL. This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University (Ethics No. 2024215X). RESULTS: Patient 1 initially presented with early-onset coronary heart disease, with initial lipid levels of serum total cholesterol (TC) 9.86 mmol/L (normal reference value: 3.10~5.20 mmol/L) and serum low-density lipoprotein cholesterol (LDL-C) 8.37 mmol/L (normal reference value: 1.27~3.12 mmol/L) on admission. Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month, but the lipid-lowering effect was not significant. The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol. After one year of treatment, the patient developed paroxysmal chest pain symptoms. A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L. The lipid-lowering regimen was continued, and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/L. Patient 2 was found to have an abnormally high blood lipid level and carotid artery hardening during physical examination, with an initial blood lipid level of serum TC 11.82 mmol/L and serum LDL-C 9.63 mmol/L. After receiving rosuvastatain therapy, the lipid-lowering effect was significant. WES revealed that patient 1 carried the heterozygous variants c.1871_1873del(p.Ile624del) and c.1747C>T (p.His583Tyr) in the LDLR gene (NM_000527.4), while patient 2 carried the heterozygous variants c.1747C>T (p.His583Tyr) in the LDLR gene and c.6936_6937inv (p.Ile2313Val) in the APOB gene (NM_000384). According to the ACMG Guidelines, the LDLR gene c.1747C>T (p.His583Tyr) was classified as a pathogenic variant (PS3+PM1+PM2_supporting+PM5+PP2+PP3), and c.1871_1873del (p.Ile624del) was classified as a pathogenic variant (PS3+PS4+PM2_supporting+PM1+PM4); the APOB gene c.6936_6937inv (p.Ile2313Val) was classified as a variant of uncertain clinical significance (PM2_supporting BP4). CONCLUSION Patients 1 and 2 in this study were patients with complex heterozygous variant FH, and their genotypic differences may be related to the differences in clinical serum LDL-C levels and the efficacy of hypolipidemic agents.
Humans ; Hyperlipoproteinemia Type II/drug therapy* ; Male ; Female ; Heterozygote ; Adult ; Middle Aged ; Receptors, LDL/genetics* ; Retrospective Studies ; Mutation ; Exome Sequencing

In recent studies, the reported prevalence of heterozygous familial hypercholesterolemia (FH) has been higher than in previous reports. Although cascade genetic screening is a good option for efficient identification of affected patients, diagnosis using only clinical criteria is more common in real clinical practice. Cardiovascular risk is much higher in FH patients due to longstanding low density lipoprotein cholesterol (LDL-C) burden and is also influenced by other risk factors. Although guidelines emphasize aggressive LDL-C reduction, the majority of patients cannot reach the LDL-C goal by conventional pharmacotherapy. Novel therapeutics such as proprotein convertase subtilisin/kexin type 9 inhibitors have shown strong lipid lowering efficacy and are expected to improve treatment results in FH patients.
Cholesterol, LDL ; Coronary Disease ; Diagnosis* ; Drug Therapy ; Genetic Testing ; Genetics ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Hyperlipoproteinemia Type II* ; Prevalence ; Proprotein Convertases ; Risk Factors

While introducing the indications of low-density lipoprotein (LDL) apheresis, LDL absorption systems were reviewed generally. As the key components for binding LDL, four kinds of ligands which are synthesized by different principles are: 1. Positively charged peptides designed according to state charge force between ligand and LDL; 2. Peptides designed according to structural characteristics of the binding site between LDL and its receptors; 3. Antibody of Lp (a) obtained by immunizing mammals with designed peptides with the characteristics of Lp (a); 4. Segments of LDL binding proteins (LBPs) synthesized with genetic engineering method based on the specific binding of LBPs to LDL. Requirements of matrices carrying these ligands are also considered. Finally, future developments in treatments of familial hypercholesterolemia by means of blood purification using synthesized peptides are overlooked.
Adsorption ; Drug Carriers ; Drug Design ; Female ; Hemoperfusion ; instrumentation ; methods ; Humans ; Hyperlipoproteinemia Type II ; blood ; therapy ; Ligands ; Lipoproteins, LDL ; blood ; isolation & purification ; Male ; Peptides ; chemical synthesis ; therapeutic use ; Receptors, LDL ; chemistry

Familial Hypercholesterolemia is the most common hyperlipoproteinemia during the childhood, which occurs from the mutation of genes that regulates low-density lipoproteins (LDL), and is classified into two types, the homozygote presented abnormal genes from both parents and the heterozygote presented an abnormal gene from each parent. Type IIa familial hypercholesterolemia is characterized by, especially, increased level of LDL which is common type and normal level of high-density lipoproteins. The clinical signs are arterosclerosis, xanthoma of the Achilles tendons and the arcus cornea. The treatments are dietary and drug therapy. This report is a case of familial hypercholesterolemia diagnosed as type IIa hyperlipoproteinnemia with Insulin Dependent Diabetes Mellitus.
Achilles Tendon ; Cornea ; Diabetes Mellitus* ; Drug Therapy ; Heterozygote ; Homozygote ; Humans ; Hyperlipoproteinemia Type II* ; Hyperlipoproteinemias ; Insulin ; Lipoproteins, HDL ; Lipoproteins, LDL ; Parents ; Xanthomatosis

We report two cases of hyperlipoproteinernia(HLP) with various cutaneous xanthomas. Case 1 was a 12-year-old girl, who had tuberous, tendinous, and plane cutaneous xanthomas and corneal arcus of the left eye. Case 2 was a 40-year-old man, who had tuberous, eruptive, and plane cutaneous xanthomas. Serum lipid and lipoprotein analysis reveoled patterns of Type IIa HLP in case 1 and, of Type IIb HLP, in case 2. They have been treated with diet control and hypolipidemic drugs and are under our continuing medical supervision.
Adult ; Child ; Female ; Humans ; Hyperlipoproteinemia Type II/diagnosis* ; Hyperlipoproteinemia Type II/drug therapy* ; Hypolipidemic Agents/therapeutic use* ; Lipoproteins ; Man ; Xanthomatosis/diagnosis ; Xanthomatosis/drug therapy