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Origin of pathogenic variant and mosaicism in families with a sporadic case of haemophilia B

Mårtensson, Annika LU ; Letelier, Anna LU ; Manderstedt, Eric LU ; Glosli, Heidi and Ljung, Rolf LU orcid (2024) In Haemophilia
Abstract

Introduction: Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B. Aim: The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers. Methods: The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet... (More)

Introduction: Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B. Aim: The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers. Methods: The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique. Results: In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather. Conclusion: The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X-chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
ddPCR, F9 gene, factor IX, haemophilia, haemophilia B, mosaicism, X-chromosome
in
Haemophilia
publisher
Wiley-Blackwell
external identifiers
  • pmid:38632836
  • scopus:85191016976
ISSN
1351-8216
DOI
10.1111/hae.15019
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.
id
04fce44c-432b-4db9-8d47-b55a4075a659
date added to LUP
2024-05-02 11:39:58
date last changed
2024-05-16 12:56:32
@article{04fce44c-432b-4db9-8d47-b55a4075a659,
  abstract     = {{<p>Introduction: Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B. Aim: The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers. Methods: The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique. Results: In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather. Conclusion: The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X-chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant.</p>}},
  author       = {{Mårtensson, Annika and Letelier, Anna and Manderstedt, Eric and Glosli, Heidi and Ljung, Rolf}},
  issn         = {{1351-8216}},
  keywords     = {{ddPCR; F9 gene; factor IX; haemophilia; haemophilia B; mosaicism; X-chromosome}},
  language     = {{eng}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Haemophilia}},
  title        = {{Origin of pathogenic variant and mosaicism in families with a sporadic case of haemophilia B}},
  url          = {{http://dx.doi.org/10.1111/hae.15019}},
  doi          = {{10.1111/hae.15019}},
  year         = {{2024}},
}