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Targeted re-sequencing of F8, F9 and VWF: characterization of Ion Torrent data and clinical implications for mutation screening.
Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap. Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin.
Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap. rosanna.nilsson@hkr.se .
Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
Skåne University Hospital.
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4Article in journal (Refereed) Published
Abstract [en]

Mutations are not identified in ~5% of hemophilia A and 10-35% of type 1 VWD patients. The bleeding tendency also varies among patients carrying the same causative mutation, potentially indicating variants in additional genes modifying the phenotype that cannot be identified by routine single-gene analysis. The F8, F9 and VWF genes were analyzed in parallel using an AmpliSeq strategy and Ion Torrent sequencing. Targeting all exonic positions showed an average read depth of >2000X and coverage close to 100% in 24 male patients with known disease-causing mutations. Discrimination between reference alleles and alternative/indel alleles was adequate at a 25% frequency threshold. In F8, F9 and VWF there was an absolute majority of all reference alleles at allele frequencies >95% and the average alternative allele and indel frequencies never reached above 10% and 15%, respectively. In VWF, 4-5 regions showed lower reference allele frequencies; in two regions covered by the pseudogene close to the 25% cut-off for reference alleles. All known mutations, including indels, gross deletions and substitutions, were identified. Additional VWF variants were identified in three hemophilia patients. The presence of additional mutations in 2 out of 16 (12%) randomly selected hemophilia patients indicates a potential mutational contribution that may affect the disease phenotype and counseling in these patients. Parallel identification of disease-causing mutations in all three genes not only confirms the deficiency, but differentiates phenotypic overlaps and allows for correct genetic counseling.

Place, publisher, year, edition, pages
2019. Vol. 14, no 4
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Biological Sciences
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URN: urn:nbn:se:hkr:diva-19258DOI: 10.1371/journal.pone.0216179ISI: 000465846200037PubMedID: 31026269OAI: oai:DiVA.org:hkr-19258DiVA, id: diva2:1313670
Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-23Bibliographically approved

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Manderstedt, EricNilsson, RosannaLind-Halldén, ChristinaHalldén, Christer
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