Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia

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dc.contributor.author Benedek, P.
dc.contributor.author Jiao, H.
dc.contributor.author Duvefelt, K.
dc.contributor.author Skoog, T.
dc.contributor.author Linde, M.
dc.contributor.author Kiviluoma, P.
dc.contributor.author Kere, J.
dc.contributor.author Eriksson, M.
dc.contributor.author Angelin, B.
dc.date.accessioned 2022-02-16T11:45:01Z
dc.date.available 2022-02-16T11:45:01Z
dc.date.issued 2021-08
dc.identifier.citation Benedek , P , Jiao , H , Duvefelt , K , Skoog , T , Linde , M , Kiviluoma , P , Kere , J , Eriksson , M & Angelin , B 2021 , ' Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia ' , Journal of internal medicine , vol. 290 , no. 2 , pp. 404-415 . https://doi.org/10.1111/joim.13287
dc.identifier.other PURE: 165166809
dc.identifier.other PURE UUID: 3962a9c3-c1b5-421c-945d-56f569899f32
dc.identifier.other WOS: 000647413400001
dc.identifier.uri http://hdl.handle.net/10138/340404
dc.description.abstract 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. en
dc.format.extent 12
dc.language.iso eng
dc.relation.ispartof Journal of internal medicine
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Familial hypercholesterolaemia
dc.subject genotyping
dc.subject next-generation sequencing
dc.subject precision medicine
dc.subject APOB
dc.subject LDLR
dc.subject PCSK9
dc.subject 3121 General medicine, internal medicine and other clinical medicine
dc.title Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia en
dc.type Article
dc.contributor.organization STEMM - Stem Cells and Metabolism Research Program
dc.contributor.organization Juha Kere / Principal Investigator
dc.contributor.organization Research Programs Unit
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1111/joim.13287
dc.relation.issn 0954-6820
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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