Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease

Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease - Ahmad - 2014 - Haemophilia - Wiley Online Library Skip to Main Content Log in / Register Log In E-Mail Address Password Forgotten Password?

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Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand diseaseF. Ahmad1,2,*, F. Oyen3, R. Jan1, U. Budde4, R. Schneppenheim3 andR. Saxena1,*Article first published online: 8 APR 2014

DOI: 10.1111/hae.12441

© 2014 John Wiley & Sons Ltd

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HaemophiliaEarly View (Online Version of Record published before inclusion in an issue)

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How to CiteAhmad, F., Oyen, F., Jan, R., Budde, U., Schneppenheim, R. and Saxena, R. (2014), Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease. Haemophilia. doi: 10.1111/hae.12441

Author Information1

Department of Haematology, All India Institute of Medical Sciences (AIIMS), New Delhi, India

2

Center for Translational Medicine, School of Medicine Temple University, Philadelphia, PA, USA

3

Department of Pediatric Haematology Oncology, University Medical Centre Hamburg Eppendorf, Hamburg, Germany

4

Hämostaseology, Medilys Laborgesellschaft mbH, Hamburg, Germany

* Correspondence: Firdos Ahmad, PhD, Center for Translational Medicine, School of Medicine Temple University, 3500 N Broad Street, Philadelphia, PA 19140, USA.
Tel.: +1 215 707 6518; fax: +1 215 707 9820;
e-mail: firdos.ahmad@temple.edu
Renu Saxena, MD, Professor and Head, Department of Hematology, All India Institute of Medical Sciences, New Delhi, India 110029.
Tel: +91-11-2659 4670 Fax: +91-11-2658 8663
e-mail: renusaxena@outlook.com

Publication HistoryArticle first published online: 8 APR 2014Manuscript Accepted: 17 MAR 2014Funded byDepartment of Science and TechnologyIndian Council of Medical Research New DelhiUniversity Medical Center Hamburg SEARCH Search Scope All contentPublication titlesIn this journalIn this issue Search String Advanced >Saved Searches > SEARCH BY CITATION Volume: Issue: Page: ARTICLE TOOLSGet PDF (188K)Save to My ProfileE-mail Link to this ArticleExport Citation for this ArticleGet Citation AlertsRequest Permissions AbstractArticleReferencesCited By View Full Article (HTML) Enhanced Article (HTML) Get PDF (188K) Keywords:carrier detection; de novo ;germline mutations;linkage markers;VWD;VWF multimerSummary

Linkage analysis in autosomal inherited von Willebrand disease (VWD) is important to diagnose the carriers and reduce the burden of severe type VWD. The study was designed to identify the carriers and estimate the frequency of variable number of tandem repeats (VNTR) instability in VWD families. Carrier detection was performed in eight recessive type 3 VWD (VWD3) families using VNTRs VWF1 and VWF2, RsaI (789Thr/Ala) linkage markers, multimer analysis and DNA sequencing. Moreover, five dominant VWD families were studied through DNA sequencing and multimer analysis. Frequency of VWF VNTR instability was investigated in 20 VWD families. In VWD3 families, a total of 22 (81.5%) carriers were identified using VWF1 and VWF2 markers. However, only 13(48.1%) carriers were identified through RsaI markers. Mutation screening revealed 22(81.5%) carriers in VWD3 and 4 (33.3%) carriers in VWD2 families. In comparison to DNA sequencing, the accuracy of VWF1 and VWF2 markers in VWD3 was 85.7% while RsaI could identify 68.2% carriers accurately. Mutations p.R1205H and p.C1272R were identified as de novo in families. Multimer analysis confirmed the identified carriers in VWD2 families. Three VWD families were found to be carrying VNTR instability for VWF1 and VWF2 locus. VNTRs could be an effective linkage markers for carrier detection in VWD3 families. However, in the event of germline de novo mutations and VNTR instability, it may confound risk of misdiagnosis of carriers. Multimer analysis could be an alternative way of carrier detection in dominant type 2A and type 2B VWD families.

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