Haemophilia in Sweden – Studies on mutations and clinical implications

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 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).