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Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease
Author(s) -
Ahmad F.,
Oyen F.,
Jan R.,
Budde U.,
Schneppenheim R.,
Saxena R.
Publication year - 2014
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/hae.12441
Subject(s) - von willebrand disease , genetics , locus (genetics) , genetic linkage , variable number tandem repeat , medicine , dna sequencing , germline mutation , dna , biology , mutation , von willebrand factor , immunology , genotype , gene , platelet
Summary 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 ( VWD 3) families using VNTR s VWF1 and VWF 2, Rsa I (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 VWD 3 families, a total of 22 (81.5%) carriers were identified using VWF 1 and VWF 2 markers. However, only 13(48.1%) carriers were identified through Rsa I markers. Mutation screening revealed 22(81.5%) carriers in VWD 3 and 4 (33.3%) carriers in VWD 2 families. In comparison to DNA sequencing, the accuracy of VWF 1 and VWF 2 markers in VWD 3 was 85.7% while Rsa I 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 VWD 2 families. Three VWD families were found to be carrying VNTR instability for VWF 1 and VWF 2 locus. VNTR s could be an effective linkage markers for carrier detection in VWD 3 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.