Haemophilia: strategies for carrier detection and prenatal diagnosis* I.R. Peake,1 D.P. Lillicrap,2 V. Boulyjenkov,3 E. Briet,4 V. Chan,5 E.K. Ginter,6 E.M. Kraus,7 R. Ljung,8 P.M. Mannucci,9 K. Nicolaides,10 & E.G.D. Tuddenham1l In 1977 WHO published in the Bulletin a Memorandum on Methods for the Detection of Haemophilia Carriers. This was produced following a WHO/WFH (World Federation of Haemophilia) Meeting of Investigators in Geneva in November 1976, and has served as a valuable reference article on the gene- tics of haemophilia. The analyses discussed were based on phenotypic assessment, which, at that time, was the only procedure available. The molecular biology revolution in genetics during the 1980s made enormous contributions to our understanding of the molecular basis of the haemophilias and now permits precise carrier detection and prenatal diagnosis. WHO and WFH held a joint meeting on this subject in February 1992 in Geneva. This article is the result of these discussions. Assessment of the problem gene from the other parent the clotting factor level is around 50% of normal, which is generally sufficient The carrier state in haemophilia for normal haemostasis. Clinical and genetic considerations. Carriers of Symptoms of bleeding do occur, however, in haemophilia usually inherit their abnormal factor carriers if their clotting factor level is in the range of VIII or factor IX gene from one of their parents. mild haemophilia, below 40%. This may be due to Since they have a second normal X-chromosomal homozygosity, Turner's syndrome, other chromo- somal abnormalities, extreme lionization, or the co-inheritance of a variant von Willebrand factor * Based on the report of a WHO/WFH meeting in Geneva, allele (i.e., von Willebrand's disease Normandy). 10-12 February 1992 (unpublished document No. WHO/HDP/ With the increasing success of patient associations, WFH/92.4). the chances of carriers marrying patients might be 1 Department of Medicine and Pharmacology, Royal Hallamshire expected to rise, but until now, homozygosity has Hospital, Sheffield, England. been distinctly rare, just as the unlikely coincidence 2 Department of Pathology, Richardson Laboratory, Queen's of Turner's syndrome and carriership. Occasional University, Kingston, Ontario, Canada. true heterozygous carriers with low clotting factor 3 Hereditary Diseases Programme, World Health Organization. 1211 Geneva 27, Switzerland. Requests for reprints should be levels due to extreme lionization, however, are sent to this address. known in all major haemophilia centres. Within the 4 Haemostasis and Thrombosis Centre, University Hospital, perspective of this article, this is relevant for invas- Leiden, Netherlands. ive procedures for prenatal diagnosis and for the 5 University of Hong Kong, Department of Medicine, Queen management of delivery. Mary Hospital, Hong Kong. Anxiety about the risk of haemophilia affecting 6 Institute of Clinical Genetics, National Research Centre of their offspring is the reason why possible carriers Medical Genetics, Moscow, Russian Federation. seek advice. The first step in this genetic counselling 7 New England Haemophilia Centre, The Medical Centre of Central Massachusetts Memorial, Worcester, MA, USA. procedure is to find out why the consultand thinks 8 Department of Paediatrics, Malmo General Hospital, Malmo, that she might carry the gene. This may lead to any Sweden. of three conclusions: she is not a carrier, she is an 9 A Bianchi Bonomi Haemophilia & Thrombosis Centre, Milan, obligatory carrier, she is a possible carrier. Italy. Carriership is excluded if haemophilia occurs in 10 Harris Birthright Research Centre for Fetal Medicine, King's the paternal family without her father himself being College Hospital School of Medicine & Dentistry, London, affected. Carriership is obligatory if her father has England. haemophilia or if she has maternal relatives with " Clinical Research Centre, Harrow, Middlesex, England. haemophilia as well as an affected child. In these Reprint No. 5402 situations each newborn son has a 50% chance of Bulletin of the World Health Organization, 71 (3/4): 429-458 (1993) © World Health Organization 1993 429 I.R. Peake et al. being affected. If the consultand has more than one may have different perceptions regarding carrier son with haemophilia without other affected rela- testing. In the case of mild clinical disease in the tives, she may be either a true heterozygote, or a family, women may see no need for carrier testing mosaic (1-4). In the case of somatic or germline because of perceptions that haemophilia will not have mosaicism the recurrence risk of the disease in sub- a large personal impact. Those with more distantly sequent newborn sons depends on the proportion of related haemophilic relatives may be eager to pursue ova carrying the abnormal gene, which is difficult to testing because of a perceived low risk, but may be establish. Carriership is possible if the consultand unprepared if positive results are obtained. has affected relatives on the maternal side and no It is important that formal counselling be done affected children, or if she has one affected son and before laboratory tests are even considered, in order no other affected relatives. In the last case, there are to resolve conflicts that may exist between a four possibilities: the consultand may have inherited woman's desire to learn of her carrier status and the the gene through the silent maternal line, which implications of possible results. It should be empha- makes her a true heterozygote; she may be a mosaic; sized that the results of carrier testing may also be the affected son may have received the abnormal that the woman is not a carrier of haemophilia. The gene from a mutation in the single ovum that he anxieties a woman might have regarding genetic test- originated from; or, the affected son may himself be ing may also be complicated by the type of testing a somatic mosaic with a large proportion of factor available and the requirements of such, as well as the VIII- or IX-producing cells carrying the mutation reliability of the tests involved. The possibility of (5). inconclusive test results, or results that are not highly After this first step, the genetic counsellor pro- accurate may deter some women from choosing to be ceeds with rigorous pedigree analysis, clotting factor tested. assays, and DNA studies in order to minimize uncer- Many women who choose to undergo carrier tainty and set the stage for decision-making about testing may perceive themselves as either carriers or prenatal diagnosis. These phases are described non-carriers prior to actual laboratory testing. This below. perception may influence how an individual assimi- lates the results of her laboratory testing; it is there- Psychological considerations. Every woman who fore an important issue to discuss during counselling. considers carrier testing for haemophilia, has a mul- Those who assume that they are non-carriers will be titude of sociological and psychological influences supported by negative results, but may feel shock which might affect her perceptions of the personal and surprise if given positive results. Those who implications of possible carrier status. Some assume that they are carriers may be relieved when influences may be created by the ethnic and/or reli- given negative results, but they may also feel guilty gious background of the individual. A particular for "escaping" their family's genetic burden, and society's perception of a woman who carries the they may have difficulty coping with their new status gene for haemophilia may certainly influence if life decisions have been made based on their whether or not a woman at risk chooses to be assumptions of carrier status. Women who receive tested. Decisions to undergo carrier testing may positive results will need a great deal of support, as also be dependent upon the degree of anxiety about they then must deal with the reality of their carrier haemophilia and its complications, as well as the status within the context of their family and their availability and safety of treatment. Women who society. live in countries where treatment for haemophilia is inadequate, may be very interested in carrier detec- Prenatal diagnosis tion and prenatal diagnosis, and therefore a more agressive approach to testing may be successful. Clinical and genetic considerations. In families at Preconceived notions about the clinical aspects risk of having a child with haemophilia, assessment of the disease will be formed as a result of the degree of carrier status and counselling regarding prenatal of, and content of contact with male haemophilic diagnosis should ideally be carried out before relatives. Women who have male relatives with more conception. Pregnant carriers requesting prenatal clinically severe disease, with inhibitors, or AIDS, diagnosis should be counselled as to the avail- may be more inclined to seek out carrier testing. This able options, including the techniques for fetal is especially true if individuals have been able to tissue sampling, their limitations, and potential closely observe the effects of the disease on them- complications. If the fetus is affected, the options selves and their family over time. Women who are of (i) continuing with the pregnancy and either keep- related to those with milder clinical disease, or who ing or adopting their child, and (ii) terminating the have more distantly related haemophilic relatives, pregnancy, are reviewed. 430 WHO Bulletin OMS. Vol 71 1993 Haemophilia: carrier detection and prenatal diagnosis Diagnostic centres. Prenatal diagnosis should be Genetic diagnosis undertaken in centres with full genetic, haemotologi- cal and obstetric expertise. Assessment of carrier status Diagnostic tests. In the early days of prenatal diagno- Family data: risk assessment. A pedigree of the sis of the haemophilias (until the mid 1980s) the family has to be carefully drawn with accurate infor- policy was to perform amniocentesis at 16 weeks mation on the males being affected with haemophilia followed by fetal blood sampling at 20 weeks for or not.