Summary
To investigate the sporadic occurrence of hemophilia A and to estimate the sex ratio of mutation rates directly, 17 families with isolated cases of the disorder were studied by RFLP analysis and by clotting assays. Three RFLPs, one intragenic and two with close linkage to hemophilia A, were used. In eight families the RFLP study excluded the carrier status of the maternal grandmothers. Since hemostatic studies showed that the eight mothers of these propositi were hemophilia carriers, the origin of the newly mutated genes was inferred from the RFLP patterns: six hemophilic genes derived from the normal maternal grandfathers and two, from maternal grandmothers. The data indicate a higher mutation rate in males than in females, as previously suggested by segregation analysis and coagulation studies. However the sex ratio indicated by the RFLP analysis is lower than previously reported and could explain previous conflicting estimates.
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References
Barrai I, Cann HM, Cavalli-Sforza LL, Barbujani G, De Nicola P (1985) Segregation analysis of haemophilia A and B. Am J Hum Genet 37:680–699
Biggs R, Rizza CR (1976) The sporadic case of haemophilia A. Lancet II:431–433
Buffone GJ, Darlington GJ (1985) Isolation of DNA from biological specimens without extraction with phenol. Clin Chem 31:164–165
Danieli GA, BarbujaniG (1984) Duchenne muscular dystrophy. Frequency of sporadic cases. Hum Genet 67:252–256
Del Senno L, Degli Uberti E, Rossi M, Buzzoni D, Barbieri R, Rossi P, PatracchiniP, Bernardi F, Marchetti G, Conconi F, Gambari R (1986) Identification of a c-myc oncogene lacking the exon 1 in the normal cells of a patient carrying a thyroid carcinoma. FEBS Lett 196:296–300
Driscoll MC, Miller CH, Goldberg JD, Aledort LM, Hoyer LW, Golbus MS (1986) Recombination between factor VIII: C gene and St14 locus. Lancet I:279
GitschierJ, Drayna D, Tuddenham EGD, White RL, Lawn RM (1985a) Genetic mapping and diagnosis of haemophilia A achieved through a Bcl I polymorphism in the factor VIII gene. Nature 314:738–740
GitschierJ, Wood WJ, Tuddenham EDG, Schuman MA, Goralka TM, Chen EY, Lawn RM (1985b) Detection and sequence of mutations in the factor VIII gene of haemophiliacs. Nature 315:427–432
Haldane JBS (1935) The rate of spontaneous mutations of a human gene. J Genet 31:317–326
Haldane JBS (1947) The mutation rate of the gene for haemophilia and its segregation in males and females. Ann Eugen (Lond) 13: 262–271
Harper K, Winter RM, Pembrey ME, Hartley D, Davies KE, Tuddenham EGD (1984) A clinically useful DNA probe closely linked to haemophilia A Lancet II:6–8
Janco RL, Phillips JA, Orlando P, Davies KE, Old J, Antonarakis SE (1986) Carrier testing strategy in haemophilia A. Lancet I:148–149
Kosower N, Christiansen R, Morton NE (1962) Sporadic cases of haemophilia and the question of a possible sex difference in mutation rates. Am J Hum Genet 14:159–169
Lehesjoki AE, De La Chapelle A, Rasi V (1986) Haemophilia A: two recombinations detected with probe St 14. Lancet I:280
Maniatis T, Fritsch EF Sambrook J (eds) (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Oberle I, Camerino G, Heiling R, Grunebaum L, Cazenave JP, Crapanzano C, Mannucci P, Mandel JL (1985) Genetic screening for hemophilia A (classic hemophilia) with a polymorphic DNA probe. N Engl J Med 312:682–686
Panicucci F, Baicchi U, Sagripanti A, Pinori E, Bruno V (1974) Detection of carriers of haemophilia. IX Congress of the WFH, Istanbul 1974, p 42 (abstr)
Panicucci F, Baicchi U, Sagripanti A, Pinori E, Lecchini L (1975) Detection of carriers of haemophilia. In: Ulutin ON, Peake IR (eds) Haemophilia. Excerpta Medica, Amsterdam, pp 52–59
Panicucci F, Baicchi U, Sagripanti A, Pinori E, Lecchini L (1976) Detection of haemophilia carriers in Italy using linear discriminant analysis. Proceedings of the XI Congress of the WFH, Kyoto 1976, pp 299–302
Peake IR, Bloom AL (1986) Recombination between genes and closely linked polymorphisms Lancet II:1335
Peake IR, Lillicrap DP, Liddel MB, Matthews RJ, Bloom AL (1985) Linked and intragenic probes for haemophilia A. Lancet II:1003–1004
Ratnoff O, Jones PK (1977) The laboratory diagnosis of the carrier state for classic haemophilia. Ann Int Med 86:521–528
Vogel F (1977) A probable sex difference in some mutation rates. Am J Hum Genet 29:312–319
Vogel F, Rathenberg R (1975) Spontaneous mutation in men. In: Harris H, Hirschorn K (eds) Advances in human genetics. Plenum Press, New York, pp 223–318
Winter RM, Tuddenham EGD, Goldman E, Matthews KB (1984) A maximum likelihood estimate of the sex ratio of mutation rates in haemophilia A. Hum Genet 64:156–159
Winter RM, Harper K, Goldman E, Mibashan RS, Warren RC, Rodeck CH, Penketh RJA, Ward RHT, Hardisty RM, Pembrey ME (1985) First trimester prenatal diagnosis and detection of carriers of haemophilia A using the linked DNA probe DX13. Br Med J [Clin Res] 291:765–769
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Bernardi, F., Marchetti, G., Bertagnolo, V. et al. RFLP analysis in families with sporadic hemophilia A. Hum Genet 76, 253–256 (1987). https://doi.org/10.1007/BF00283618
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DOI: https://doi.org/10.1007/BF00283618