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Copy number variants in familial hypercholesterolemia genes using targeted NGS, validated through optical genome mapping
Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
Bionano Genomics, Evry Cedex, France.
Örebro University, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro, Sweden.
Örebro University, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro, Sweden.
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2024 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 32, no Suppl. 1, p. 159-159, article id EP06.039Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background/Objectives: Familial hypercholesterolemia (FH) is a common genetic disorder which is primarily caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. Approximately 10% of pathogenic variants in LDLR may be CNVs. Here, we combine NGS, MLPA, and Optical Genome Mapping (OGM) to investigate CNVs in LDLR.

Methods: A NGS panel was designed for whole gene sequencing (8 genes) of 100 FH patients using Twist technology and Illumina platform. CNVs were detected using CNVexpo, and an in-house pipeline for base-resolved normalized coverage. Identified CNVs were validated using MLPA and OGM. Bionano Services Lab performed the OGM procedure. Purified gDNA was labeled using Direct Label and Stain DNA Labeling Kit. Saphyr chip was run aiming for 100X coverage. De novo assembly and Variant Annotation pipelines were executed on Bionano Solve v3.7. Bionano Access v1.7 was used for CNV reporting and visualization.

Results: In five out of 100 samples NGS and MLPA data showed heterozygous deletions in LDLR. Three deletions, affecting different exons, was analyzed and confirmed using OGM. In two samples, OGM better defined the breakpoints as well as the size of the event, which expanded far beyond the gene of interest. In one sample, an additional CNV of SLCO1B1, a pharmaco-gene, important for transport of statins used for FH treatment was identified.

Conclusion: CNVs in FH genes in FH patients could be detected using targeted NGS, which was further confirmed by MLPA and characterized using OGM.

Place, publisher, year, edition, pages
Nature Portfolio , 2024. Vol. 32, no Suppl. 1, p. 159-159, article id EP06.039
National Category
Medical Genetics and Genomics
Identifiers
URN: urn:nbn:se:oru:diva-112042ISI: 001147414900426OAI: oai:DiVA.org:oru-112042DiVA, id: diva2:1842247
Conference
56th Annual Conference of the European-Society-of-Human-Genetics (ESHG), Glasgow, Scotland, June 10-13, 2023
Note

The study received grants from Örebro County Research Committee.

Available from: 2024-03-04 Created: 2024-03-04 Last updated: 2025-02-10Bibliographically approved

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Green, AnnaAdolfsson, EmmaNordenskjöld, Anna M.

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