Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study

Autor: Michelle Xueqin Lin, Su Chi Lim, Subramaniam Tavintharan, Hean Yee Ong, Jessie Choi Wan Fong, Justin I-Shing Tang, Sharon Li Ting Pek, Chee Fang Sum, Chee Wan Lee, Eric Zit Liang Chan, Sanjaya Dissanayake
Rok vydání: 2018
Předmět:
Adult
Genetic Markers
Male
0301 basic medicine
Proband
medicine.medical_specialty
Apolipoprotein B
DNA Mutational Analysis
Familial hypercholesterolemia
030204 cardiovascular system & hematology
medicine.disease_cause
Gastroenterology
Frameshift mutation
Hyperlipoproteinemia Type II
Young Adult
03 medical and health sciences
0302 clinical medicine
Internal medicine
medicine
Humans
Genetic Predisposition to Disease
Singapore
Mutation
biology
business.industry
PCSK9
Point mutation
High-Throughput Nucleotide Sequencing
Cholesterol
LDL
Middle Aged
medicine.disease
Phenotype
030104 developmental biology
Receptors
LDL
Apolipoprotein B-100
biology.protein
Female
lipids (amino acids
peptides
and proteins)
Proprotein Convertase 9
Cardiology and Cardiovascular Medicine
business
Multiplex Polymerase Chain Reaction
Biomarkers
Zdroj: Atherosclerosis. 269:106-116
ISSN: 0021-9150
Popis: Background and aims Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by the presence of high plasma low density lipoproteins cholesterol (LDL-c). Patients with FH, with mutation detected, are at increased risk of premature cardiovascular disease compared to those without mutations. The aim of the study was to assess the type of mutations in patients, clinically diagnosed with FH in Singapore. Methods Patients (probands) with untreated/highest on-treatment LDL-c>4.9 mmol/l were recruited (June 2015 to April 2017). Anthropometric, biochemical indices, blood and family history were collected. DNA was extracted and Next Generation Sequencing (NGS) was performed in 26 lipid-related genes, including LDLR, APOB and PCSK9, and validated using Sanger. Multiplex-ligation probe analyses for LDLR were performed to identify large mutation derangements. Based on HGVS nomenclature, LDLR mutations were classified as “Null”(nonsense, frameshift, large rearrangements) and “Defective”(point mutations which are pathogenic). Results Ninety-six probands were recruited: mean age: (33.5 ± 13.6) years. 52.1% (n = 50) of patients had LDLR mutations, with 15 novel mutations, and 4.2% (n = 4) had APOB mutations. Total cholesterol (TC) and LDL-c were significantly higher in those with LDLR mutations compared to APOB and no mutations [(8.53 ± 1.52) vs. (6.93 ± 0.47) vs. (7.80 ± 1.32)] mmol/l, p = 0.012 and [(6.74 ± 0.35) vs. (5.29 ± 0.76) vs. (5.98 ± 1.23)] mmol/l, p=0.005, respectively. Patients with “null LDLR” mutations (n = 13) had higher TC and LDL-c than “defective LDLR” mutations (n = 35): [(9.21 ± 1.60) vs. (8.33 ± 1.41)]mmol/l, p = 0.034 and [(7.43 ± 1.47) vs. (6.53 ± 1.21)]mmol/l, p=0.017, respectively. Conclusions To our knowledge, this is the first report of mutation detection in patients with clinically suspected FH by NGS in Singapore. While percentage of mutations is similar to other countries, the spectrum locally differs.
Databáze: OpenAIRE
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