Genetics 101: understanding transmission and genetic testing of inherited bleeding disorders

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Abstract

Haemophilia is an X-linked inherited disorder that affects males and females, though the bleeding risk in girls and women has traditionally been under-recognised. About one third of haemophilia cases occur in individuals where there is no known family history. The gene mutations for rare bleeding disorders are not carried on the X chromosome and are therefore not sex-linked; however, the risk of passing on the condition is greatly increased for consanguineous parents where both parents may carry a copy of the fault in the genetic code which causes the condition. Genetic testing should be offered to every prospective mother, ideally before conception. This should be supported by counselling as the implications for family planning are profound.

Von Willebrand factor (VWF) has an important role in primary and secondary haemostasis. Loss of function or low levels of VWF are associated with spontaneous bleeding causing nosebleeds, heavy periods and bruising as well as jpost-surgical bleeding. Joint bleeding and intracranial haemorrhage can also occur in those with a severe type of VWF. Diagnosis depends on bleeding assessment, family history and measurement of VWF. There are three types of VWD: Types 1 and 3 are caused by low or absent levels of VWD; Type 2 is caused by loss of function. Of these, Type 3 VWD is associated with the most severe bleeding risk but there is wide variation in bleeding phenotype among the other sub-types. The correlation between genetic mutation and bleeding phenotype is weak in VWD; therefore genetic testing is mainly useful for interpreting the risk when planning a family and to allow prenatal diagnosis in severe bleeding disorders.

Genetic testing is essential for prospective parents to make fully informed decisions about having a family and how or whether to proceed with a pregnancy. The rationale for prenatal testing is to determine the bleeding status of the foetus and to inform decisions about managing delivery. Women may choose to terminate a pregnancy to avoid having a child with severe haemophilia. For some couples the option of adoption or not having children may be explored. Options for prenatal diagnostic testing include non-invasive methods, e.g. assessment of free foetal DNA in maternal plasma to determine the sex of a baby from 10 weeks in pregnancy, and invasive methods, e.g. chorionic villus sampling or amniocentesis, to determine the inheritance of the genetic mutation. Invasive methods are associated with a very small increased risk of pregnancy loss or early labour, which many couples feel is an unacceptable risk. Advanced techniques such as preimplantation screening also available, but require a huge commitment as this involves an IVF technique.

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  • 1. Kasper CK Lin JC. Prevalence of sporadic and familial haemophilia. Haemophilia 2007; 13: 90-2.

  • 2. Mårtensson A Ivarsson S Letelier A et al. Origin of mutation in sporadic cases of severe haemophilia A in Sweden. Clin Genet 2016; 90: 63-8. doi: 10.1111/cge.

  • 3. Kling S Ljung R Sjörin E et al. Origin of mutation in sporadic cases of haemophilia-B. Eur J Haematol 1992; 48: 142-5.

  • 4. Leebeek FWG Eikenboom JCJ. Von Willebrand’s disease. N Engl J Med 2017; 376: 701-2. doi: 10.1056/NEJMc1616060.

  • 5. Leebeek FW Eikenboom JC. Von Willebrand’s disease. N Engl J Med 2016; 375 :2067-2080. doi: 10.1056/NEJMra1601561.

  • 6. Veyradier A Boisseau P Fressinaud E et al. A laboratory phenotype/genotype correlation of 1167 French patients from 670 families with von Willebrand disease: a new epidemiologic picture. Medicine (Baltimore) 2016; 95: e3038. doi: 10.1097/MD.0000000000003038.

  • 7. Flood VH Christopherson PA Gill JC et al. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood 2016; 127: 2481-8. doi: 10.1182/blood-2015-10-673681.

  • 8. Boender J Eikenboom J van der Bom JG et al. Clinically relevant differences between assays for von Willebrand factor activity. J Thromb Haemost 2018; 16: 2413-24. doi: 10.1111/jth.14319.

  • 9. Atiq F Meijer K Eikenboom J et al. Comorbidities associated with higher von Willebrand factor (VWF) levels may explain the age-related increase of VWF in von Willebrand disease. Br J Haematol 2018; 182: 93-105.

  • 10. Lavin M Aguila S Schneppenheim S et al. Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels. Blood 2017; 130: 2344-53. doi: 10.1182/blood-2017-05-786699.

  • 11. de Wee EM Sanders YV Mauser-Bunschoten EP et al. Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease. Thromb Haemost 2012; 108: 683-92.

  • 12. Kadir RA Sabin CA Goldman E et al. Reproductive choices of women in families with haemophilia. Haemophilia 2000; 6: 33-40.

  • 13. Tedgård U Ljung R McNeil TF. Reproductive choices of haemophilia carriers. Br J Haematol 1999; 106: 421-6.

  • 14. Solomon G Greenberg J Futter M et al. Understanding of genetic inheritance among Xhosa-speaking caretakers of children with hemophilia. J Genet Couns 2012; 21: 726-40. doi: 10.1007/s10897-012-9495-9.

  • 15. Gillham A Greyling B Wessels TM et al. Uptake of genetic counseling knowledge of bleeding risks and psychosocial impact in a South African cohort of female relatives of people with hemophilia. J Genet Couns 2015; 24: 978-86. doi: 10.1007/s10897-015-9834-8.

  • 16. Davies JS. Women with inheruted bleeding disorders and their offspring – the unresolved issues [doctoral thesis] London: UCL 2017. Available from http://discovery.ucl.ac.uk/1547469/ (accessed 12 September 2019).

  • 17. Chi C Hyett JA Finning KM et al. Non-invasive first trimester determination of fetal gender: a new approach for prenatal diagnosis of haemophilia. BJOG 2006; 113: 239-42.

  • 18. Chi C Lee CA Shiltagh N et al. Pregnancy in carriers of haemophilia. Hemophilia 2008; 14: 56–64.

  • 19. Cutler J Chappell LC Kyle P Madan B. Third trimester amniocentesis for diagnosis of inherited bleeding disorders prior to delivery. Haemophilia 2013; 19: 904-7. doi: 10.1111/hae.12247.

  • 20. Tsui NB Kadir RA Chan KC et al. Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. Blood 2011; 117: 3684-91. doi: 10.1182/blood-2010-10-310789.

  • 21. Hudecova I Jiang P Davies J et al. Noninvasive detection of F8 int22h-related inversions and sequence variants in maternal plasma of hemophilia carriers. Blood 2017; 130: 340-7. doi: 10.1182/blood-2016-12-755017.

  • 22. Dahdouh EM Balayla J García-Velasco JA. Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertil Steril 2015; 104: 1503-12. doi: 10.1016/j.fertnstert.2015.08.038.

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