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

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http://hdl.handle.net/10138/340404

Lähdeviite

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

Julkaisun nimi: Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia
Tekijä: Benedek, P.; Jiao, H.; Duvefelt, K.; Skoog, T.; Linde, M.; Kiviluoma, P.; Kere, J.; Eriksson, M.; Angelin, B.
Tekijän organisaatio: STEMM - Stem Cells and Metabolism Research Program
Juha Kere / Principal Investigator
Research Programs Unit
Päiväys: 2021-08
Kieli: eng
Sivumäärä: 12
Kuuluu julkaisusarjaan: Journal of internal medicine
ISSN: 0954-6820
DOI-tunniste: https://doi.org/10.1111/joim.13287
URI: http://hdl.handle.net/10138/340404
Tiivistelmä: 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.
Avainsanat: Familial hypercholesterolaemia
genotyping
next-generation sequencing
precision medicine
APOB
LDLR
PCSK9
3121 General medicine, internal medicine and other clinical medicine
Vertaisarvioitu: Kyllä
Tekijänoikeustiedot: cc_by
Pääsyrajoitteet: openAccess
Rinnakkaistallennettu versio: publishedVersion


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