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Haemophilia in Sweden – Studies on mutations and clinical implications

Mårtensson, Annika LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:103.
Abstract
Introduction: Haemophilia A (HA) and B (HB) are two of our most common inherited bleeding disorders and are

due to a variety of gene mutations.

Aims: The overall objective of the present research was to perform clinical and basic scientific studies on

haemophilia in Sweden to further improve and individualise the care of haemophilia patients and their relatives.

More specific aims were: to study trends and changes for prenatal diagnosis (PND) of haemophilia (paper I); to

describe the mutation spectrum of HB and its origin in terms of the mutations being recurrent mutations or

identical by descent (IBD) (paper II); to analyse the mutation profile in HB highlighting unique mutations... (More)
Introduction: Haemophilia A (HA) and B (HB) are two of our most common inherited bleeding disorders and are

due to a variety of gene mutations.

Aims: The overall objective of the present research was to perform clinical and basic scientific studies on

haemophilia in Sweden to further improve and individualise the care of haemophilia patients and their relatives.

More specific aims were: to study trends and changes for prenatal diagnosis (PND) of haemophilia (paper I); to

describe the mutation spectrum of HB and its origin in terms of the mutations being recurrent mutations or

identical by descent (IBD) (paper II); to analyse the mutation profile in HB highlighting unique mutations and

inhibitor development alongside genotype-phenotype associations (paper III); and to define the origin of mutations

of sporadic severe cases of HA.

Methods and results: Through semi-structured interviews and PND-registry data, 90 PND performed by 54 women

during 1977–2013 were found. There were 27/90 haemophilia-affected foetuses of which 16 went to termination

and 11 were born (during 2000–2013). PND was used in 27/55 cases for mental preparation (paper I). Mutation

analysis found 47/77 patients to share mutations, and haplotype analysis found (51%) (24/47) to be IBD, the

majority of these were mild forms (paper II). Mutation and haplotype analysis among 113 families (each

represented by one patient) identified 32% ‘null mutations’ and 19% inhibitor among the severely affected

families, whereas the frequency of unique mutations was at least 65% (paper III). In 40/45 sporadic families the

mutation occurred within the last two generations and in 82% (23/28) the mother was hitherto an unknown carrier.

Conclusions: PND is increasingly used as a psychological preparation for having a child with haemophilia (paper

I). Mild forms of haemophilia associated with IBD have estimated ages of mutations of between two and 23

generations (paper II). A high frequency of unique mutations was found. The high number of inhibitor families is

most likely caused by many ‘null mutations’ (paper III). Due to the young age of mutations, this indicates relatives

having a low carrier risk (paper IV). (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Lassila, Riitta, Helsinki University, Finland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
haemophilia, factor VIII, factor IX, factor 8 gene, factor 9 gene, carriers, prenatal diagnosis, mutations, inhibitors, haplotype
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:103
pages
78 pages
publisher
Department of Paediatrics, Lund University
defense location
Kvinnoklinikens aula, Skånes universitetssjukhus Malmö
defense date
2015-10-16 13:00
ISSN
1652-8220
ISBN
978-91-7619-182-8
language
English
LU publication?
yes
id
4d902164-2156-4a52-b62f-9ca4fdeec9d5 (old id 7991444)
date added to LUP
2015-09-30 10:37:28
date last changed
2016-09-19 08:44:46
@phdthesis{4d902164-2156-4a52-b62f-9ca4fdeec9d5,
  abstract     = {Introduction: Haemophilia A (HA) and B (HB) are two of our most common inherited bleeding disorders and are<br/><br>
due to a variety of gene mutations.<br/><br>
Aims: The overall objective of the present research was to perform clinical and basic scientific studies on<br/><br>
haemophilia in Sweden to further improve and individualise the care of haemophilia patients and their relatives.<br/><br>
More specific aims were: to study trends and changes for prenatal diagnosis (PND) of haemophilia (paper I); to<br/><br>
describe the mutation spectrum of HB and its origin in terms of the mutations being recurrent mutations or<br/><br>
identical by descent (IBD) (paper II); to analyse the mutation profile in HB highlighting unique mutations and<br/><br>
inhibitor development alongside genotype-phenotype associations (paper III); and to define the origin of mutations<br/><br>
of sporadic severe cases of HA.<br/><br>
Methods and results: Through semi-structured interviews and PND-registry data, 90 PND performed by 54 women<br/><br>
during 1977–2013 were found. There were 27/90 haemophilia-affected foetuses of which 16 went to termination<br/><br>
and 11 were born (during 2000–2013). PND was used in 27/55 cases for mental preparation (paper I). Mutation<br/><br>
analysis found 47/77 patients to share mutations, and haplotype analysis found (51%) (24/47) to be IBD, the<br/><br>
majority of these were mild forms (paper II). Mutation and haplotype analysis among 113 families (each<br/><br>
represented by one patient) identified 32% ‘null mutations’ and 19% inhibitor among the severely affected<br/><br>
families, whereas the frequency of unique mutations was at least 65% (paper III). In 40/45 sporadic families the<br/><br>
mutation occurred within the last two generations and in 82% (23/28) the mother was hitherto an unknown carrier.<br/><br>
Conclusions: PND is increasingly used as a psychological preparation for having a child with haemophilia (paper<br/><br>
I). Mild forms of haemophilia associated with IBD have estimated ages of mutations of between two and 23<br/><br>
generations (paper II). A high frequency of unique mutations was found. The high number of inhibitor families is<br/><br>
most likely caused by many ‘null mutations’ (paper III). Due to the young age of mutations, this indicates relatives<br/><br>
having a low carrier risk (paper IV).},
  author       = {Mårtensson, Annika},
  isbn         = {978-91-7619-182-8},
  issn         = {1652-8220},
  keyword      = {haemophilia,factor VIII,factor IX,factor 8 gene,factor 9 gene,carriers,prenatal diagnosis,mutations,inhibitors,haplotype},
  language     = {eng},
  pages        = {78},
  publisher    = {Department of Paediatrics, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Haemophilia in Sweden – Studies on mutations and clinical implications},
  volume       = {2015:103},
  year         = {2015},
}