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Polymorphism J Clin Pathol: first published as 10.1136/jcp.40.9.971 on 1 September 1987. Downloaded from J Clin Pathol 1987;40:971-977 Haemophilia A: carrier detection and prenatal diagnosis by linkage analysis using DNA polymorphism E G D TUDDENHAM,* ELEANOR GOLDMAN,t A McGRAW,* P B A KERNOFFt From the *Haemostatis Research Group, Clinical Research Centre, Harrow, Middlesex, and the tHaemophilia Centre, Royal Free Hospital, London SUMMARY Restriction fragment length polymorphisms (RFLPs) within or close to the factor VIII locus are very useful for genetic linkage analysis. Such RFLPs allow a mutant allele to be tracked in a family, segregating haemophilia A even when, as is usually the case, the precise mutation causing failure to synthesise factor VIII is unknown. To date two markers tightly linked to the factor VIII locus have been described, one ofwhich is highly polymorphic and therefore informative in most kindreds. A significant crossover rate, however, does not make diagnosis absolute. Three intragenic RFLPs have been defined, which, taken together, are informative in about 70% of women, providing virtually deterministic genetic diagnosis. copyright. Diagnosis of the carrier state is an urgent clinical biopsy samples were taken by the referring centre and problem in families with a known case ofhaemophilia shipped as whole blood or tissue frozen on dry ice. A. For every affected male, on average eight female relatives will be found who have a greater or lesser SEPARATION OF DNA genetic risk of carrying the mutant allele. Risk assess- Blood anticoagulated with edetic acid in standard ment was based until recently on pedigree analysis haematology sample tubes was frozen and stored at combined with factor VIII and Von Willebrand fac- -40'C until processed. The choice of anticoagulant http://jcp.bmj.com/ tor antigen assays.' At best, about 85% accuracy of is dictated by the fact that some restriction enzymes, discrimination from the phenotype assays was including XbaI, work poorly or not at all on hepa- obtained. As a result many females at relatively low rinised samples. No deterioration of DNA over time risk opted for definitive antenatal diagnosis by means or after shipment on dry ice from Australia to the of factor VIII bioassay or antigen assay of fetoscopic United Kingdom was noted. DNA was separated as blood sample taken in the second trimester.2 The described45 and stored at -20°C until analysed. introduction of linkage analysis based on the use of intragenic DNA probes and linked DNA markers has DNA PROBES on September 29, 2021 by guest. Protected greatly improved definitive diagnosis.3 In this paper DX13 is a fragment of the X chromosome isolated we describe the DNA probes available for diagnosis from an X genomic library6 that has been shown to be of haemophilia A and give examples of their use in linked to haemophilia A7 and to the factor VIII families studied over the past two years. gene.8 The restriction fragment length polymorphism (RFLP) is detected with BglII. StJ4 is a similar fragment derived from the same Material and methods library9 and shown to be linked to haemophilia A"0 and to the factor VIII gene.8 This locus is highly poly- Families with at least one confirmed case of hae- morphic with 10 alleles detectable using TaqI. mophilia A were referred for genetic counselling to Factor VIII exon 17,18 This is a genomic Stu I/Sca the Haemophilia Centre, Royal Free Hospital, by I fragment that detects a BclI RFLP in the adjacent physicians from the United Kingdom and world wide. intron 18.8 Fig 1 shows the location of this poly- Local residents attended in person for counselling morphism. and to give blood samples. Some blood and chorion Factor VIII intron 22 Two probes (designated a 971 J Clin Pathol: first published as 10.1136/jcp.40.9.971 on 1 September 1987. Downloaded from 972 Tuddenham, Goldman, McGraw, Kernoff kb: 0 10 20 30 40 50 60 7 80 90 100 110 120 130 140 150 160 170 180 190 200 I I- I- I I II I I I I I I I I I I I I I 23 4 56 789 101112 13 14 15AWAP 232425 26 I .. ..a I 1 I a N I-1 5' 1 l -mNL -31i 1 3' f t ? BcII Xbal Bgll Restriction fragment length polymorphismsin factor VIII Fig Approximate location ofDNA polymorphisms detectable by restriction enzymes as indicated infactor VIII gene. Solid bars; exons numbered I to 2616, open bars; introns. Precise position of3' polymorphic BglI site has not been mapped. and b) detect an XbaI polymorphism in intron 22 long enough to allow sufficient meiotic crossovers to (fig 1)." randomise the distribution of alleles on all chromo- Factor VIII 3' A fragment from the 3' end of factor somes. VIII cDNA that detects a BglI polymorphic site. The Table 2 gives haplotypes for BclI and XbaI. The precise location has not been mapped (fig 1).12 haplotype -/ + (large fragment/small fragment) was rare or absent. This means that women homozygous DNA MANIPULATION for BclI - are not informative for XbaI either Probes were gel purified or separated on CsC12 because they will be homozygous for XbaI -. Fortu- gradient by standard methods13 and labelled with nately, BclI + is the common allele, and such homo- [d-32P]dCTP by calf thymus DNA priming.'4 South- zygous women (60%) have a 37-5% (2 x 0 75 x 0-25 ern blotting"5 was performed after digestion of DNA x 100) chance of being heterozygous for XbaI. Table from a patient with appropriate restriction enzymes. 3 gives the haplotypes for BclI and BglI. The chance of being heterozygous for both is reduced as the com- copyright. Results mon allele BclI + is associated with the common allele BglI +. Only those rare females who are homo- The reported incidence of the alleles for intragenic zygous for BclI + (4%) can get additional informa- and linked RFLP's varies somewhat according to tion from BglI. population and sample size. Table 1 gives percentages The net effect of these imbalances is that about based on our own series ofmainly northern European 70% of European females are informative-that is, ancestry. The largest discrepancy was the frequency of alleles at the factor VIII 3'BglI site'2 between http://jcp.bmj.com/ European and AfroCaribbean patients. In Europeans Table 2 Factor VIII BcJI-Xbal haplotypes about 80% of X chromosomes have this site-that is, 5 kb allele detected-in blacks the frequency is 74%, Haplotype No of Per cent of giving a higher expected heterozygosity rate for Bcll Xbal chromosomes chromosomes females. The cumulative heterozygosity for the three 0-8 4-8 (or 1 4) 45 61 intragenic RFLPs was not additive due to linkage dis- 0-8 6-2 15 20 1.1 4-8 (or 1-4) 0 0 equilibrium: the time elapsed from the mutation on September 29, 2021 by guest. Protected 1 1 6-2 14 19 events responsible for the DNA variations was not Table 1 Expected Probe Enzyme* Alleles kb -/+ t Frequency (%) heterozygosity (%) Factor VIII exon 17-18 Bcl I 1 1/08 22/78 34 Factor VIII intron 22 XbaI 6 2/4 8 41/59 48 Factor VIII 3' Bgl I 20/5 20/80 32 DX13 BglII 58/2 8 50/50 50 Stl4 TaqI At least 8 > 90 *RFLP's are often referred to according to enzyme, such as factor VIII BclI. t - and + refer to absence or presence of restriction site yielding large or small alleles. J Clin Pathol: first published as 10.1136/jcp.40.9.971 on 1 September 1987. Downloaded from Carrier detection and perpetual diagnosis ofhaemophilia A 973 heterozygous-at one or more polymorphic intra- polymorphic that more than 90% of females are genic sites. These women can be given firm genetic informative. It has the additional benefit of helping to advice based on linkage as the risk of crossover confirm or exclude paternity. between these markers and a putative mutation must DX13 was the first linked marker to be discovered average about 0-1% per meiosis. The total length of and is widely used. It is not very informative com- the factor VIII gene is about 200 kb or 02cM.16 The pared with Stl4 and is also subject to crossover maximum distance from marker to mutation (fig 1) is error.20 As several crossovers have affected both Stl4 130kb or about 0 - cM, equivalent to a 1/1000 cross- and DX13 they are most likely on the same side of the over rate per meiosis. factor VIII locus, which is unfortunate as no addi- For 30% of women who are non-informative with tional confidence is gained by combining them. intragenic RFLPs we must resort to linked markers. Stl4 and DX13 are at a small but important map Case histories distance from factor VIII. Table 4 gives crossover rates calculated from data sent to Dr I Peake as part In the family shown in fig 2 two sisters (III2 and I113) of an ongoing collection of data for the International have a 50% chance of carriership on pedigree. Based Society on Thrombosis and Haemostasis."7 These on the factor VIII Bcll alleles, II2 is informative with rates may be overestimates but most centres now the 0-8 allele being associated with haemophilia A in recheck antenatal diagnoses based on linked markers her father (I,) and son (III3). Therefore III2 cannot be with fetoscopic blood sampling. At least three ante- a carrier, whereas I113 is a carrier. This result is natal diagnoses based on Stl4 linkage have proved confirmed by the DX13 alleles.
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