Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia
| Autor: | K. Duvefelt, Bo Angelin, Hong Jiao, M. Linde, T. Skoog, Juha Kere, P. Benedek, Mats Eriksson, P. Kiviluoma |
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| Přispěvatelé: | STEMM - Stem Cells and Metabolism Research Program, Juha Kere / Principal Investigator, Research Programs Unit |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Genotype Apolipoprotein B precision medicine 030204 cardiovascular system & hematology medicine.disease_cause Hyperlipoproteinemia Type II PCSK9 03 medical and health sciences 0302 clinical medicine Internal Medicine medicine Humans In patient Genetic Testing Gene Genotyping Sweden Genetics Mutation biology business.industry Middle Aged Phenotype Founder Effect 3. Good health 030104 developmental biology LDLR Receptors LDL genotyping 3121 General medicine internal medicine and other clinical medicine Apolipoprotein B-100 biology.protein Female lipids (amino acids peptides and proteins) next-generation sequencing Proprotein Convertase 9 APOB business Familial hypercholesterolaemia Founder effect |
| Popis: | Aim To investigate whether genotyping could be used as a cost-effective screening step, preceding next-generation sequencing (NGS), in molecular diagnosis of familial hypercholesterolaemia (FH) in Swedish patients. Methods and results Three hundred patients of Swedish origin with clinical suspicion of heterozygous FH were analysed using a specific array genotyping panel embedding 112 FH-causing mutations in the LDLR, APOB and PCSK9 genes. The mutations had been selected from previous reports on FH patients in Scandinavia and Finland. Mutation-negative cases were further analysed by NGS. In 181 patients with probable or definite FH using the Dutch lipid clinics network (DLCN) criteria (score >= 6), a causative mutation was identified in 116 (64%). Of these, 94 (81%) were detected by genotyping. Ten mutations accounted for more than 50% of the positive cases, with APOB c.10580G>A being the most common. Mutations in LDLR predominated, with (c.2311+1_2312-1)(2514)del (FH Helsinki) and c.259T>G having the highest frequency. Two novel LDLR mutations were identified. In patients with DLCN score < 6, mutation detection rate was significantly higher at younger age. Conclusion A limited number of mutations explain a major fraction of FH cases in Sweden. Combination of selective genotyping and NGS facilitates the clinical challenge of cost-effective genetic screening in suspected FH. The frequency of APOB c.10580G>A was higher than previously reported in Sweden. The lack of demonstrable mutations in the LDLR, APOB and PCSK9 genes in similar to 1/3 of patients with probable FH strongly suggests that additional genetic mechanisms are to be found in phenotypic FH. |
| Databáze: | OpenAIRE |
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