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
(2024)
In Haemophilia
30(3).
p.774-779
- 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.
(Less)
- author
- Mårtensson, Annika
LU
; Letelier, Anna
LU
; Manderstedt, Eric
LU
; Glosli, Heidi
and Ljung, Rolf
LU
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- ddPCR, F9 gene, factor IX, haemophilia, haemophilia B, mosaicism, X-chromosome
- in
- Haemophilia
- volume
- 30
- issue
- 3
- pages
- 774 - 779
- 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
- 2024-11-01 06:25:38
@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}},
number = {{3}},
pages = {{774--779}},
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}},
volume = {{30}},
year = {{2024}},
}