Genotypes, phenotypes and whole genome sequence: Approaches from the My Life Our Future haemophilia project
Open Access
- 21 May 2018
- journal article
- research article
- Published by Wiley in Haemophilia
- Vol. 24 (S6), 87-94
- https://doi.org/10.1111/hae.13506
Abstract
Introduction Information from the genes encoding factor VIII (F8) and IX (F9) is used in reproductive planning and to inform inhibitor formation, bleeding severity and response to therapies. Advances in technology and our understanding of the human genome now allows more comprehensive methods to study genomic variation and its impact on haemophilia. Aims The My Life Our Future (MLOF) programme was begun in 2012 to provide genetic analysis and to expand research in haemophilia through a research repository. Methods MLOF enrolled haemophilia A and B patients followed at haemophilia treatment centers in the U.S., including, since 2015, known and potential genetic carriers. Initial F8 and F9 DNA analysis was performed utilizing a next generation sequencing approach which allowed simultaneous detection of F8 inversions and other variants. Candidate variants were confirmed using a second method and multiplex ligation‐dependent probe amplification was used to detect structural variants. Results The initial phase of MLOF completed enrollment in December 2017 with 11,356 patients, genetic carriers, and potential carriers enrolled. In the 9453 subjects in whom analysis is complete, 687 unique previously unreported variants were found. Simultaneous sequencing of the F8 and F9 genes resulted in identification of non‐deleterious variants previously reported as causative in haemophilia. DNA from 5141 MLOF subjects has undergone whole genome sequencing through the NHLBI TOPMed programme of the U.S. NIH. Conclusion MLOF has provided genetic information for patients and their families to help inform clinical care and has established a repository of data and biospecimens to further advance haemophilia research.Keywords
Funding Information
- Biogen
This publication has 55 references indexed in Scilit:
- Deep intronic ‘mutations’ cause hemophilia A: application of next generation sequencing in patients without detectable mutation in F8 cDNAJournal of Thrombosis and Haemostasis, 2013
- Factor VIII mutation and desmopressin‐responsiveness in 62 patients with mild haemophilia AHaemophilia, 2013
- The International Society on Thrombosis and Haematosis von Willebrand Disease Database: An UpdateSeminars in Thrombosis and Hemostasis, 2011
- Guideline on the management of haemophilia in the fetus and neonate*British Journal of Haematology, 2011
- The ‘royal disease’ mutation in a Spanish patientJournal of Thrombosis and Haemostasis, 2010
- In non‐severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case–control studyJournal of Thrombosis and Haemostasis, 2010
- Massively parallel exon capture and library-free resequencing across 16 genomesNature Methods, 2009
- Developing a new generation of tests for genotyping hemophilia‐causative rearrangements involving int22h and int1h hotspots in the factor VIII geneJournal of Thrombosis and Haemostasis, 2008
- A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levelsBlood, 2007
- Hemophilia B LeydenNew England Journal of Medicine, 1982