Direct estimate of the haemophilia B (factor IX deficiency) mutation rate and of the ratio of the sex-specific mutation rates in Sweden

Abstract

Mutation rates for X-linked recessive diseases have so far been estimated indirectly by postulating an equilibrium between the loss of defective genes caused by the low reproductive fitness of affected males and the gain resulting from new mutations. Here, for the first time, we directly estimate both the overall and sex-specific mutation rates for haemophilia B by detecting the gene defect of the families registered at the Malmö Haemophilia Centre. These represent a complete sample of the Swedish haemophilia B population (45 out of 77 pedigrees) and contain 23 families with a single affected male. Fifteen of these males had mothers available for study, and of these mothers, 13 had parents available for study. We show that 3 of the above patients and 10 of their mothers carry new mutations, and by extrapolation calculate that 8 males and 98 females should carry new haemophilia B mutations in the Swedish population (8.52 x 10(6) individuals). This leads to the following estimate of the mutation rates: overall mu = 4.1 x 10(-6); male specific nu = 2.1 x 10(-5); and female specific mu = 1.9 x 10(-6). The ratio of such male to female specific mutation rates is thus nu/mu = 11.

Mutations associated with hemophilia B in Turkish patients

“…It is suspected that local mutations or genetic differences due to different geographic and racial influences may alter the endogenous pattern of germline mutation. A similar pattern of germline mutation has been observed in the factor IX gene of a variety of races such as Danish, French, Swedish, German, British, Americans (caucasian), Koreans/Japanese, and Mexicans (Nielsen et al, 1995;Ghanem et al, 1993;Mondanton et al, 1992;Knobloch et al, 1993;Saad et al, 1994;Bottema et al, 1990;Gostout et al, 1993;Thorland et al, 1995), but a different pattern has been observed in the Chinese population (Liu et al, submitted). The initial analysis of the molecular epidemiology of recent germline mutations in the Turkish population revealed one novel deletion of base 6411 in one patient and three point mutations that were previously observed in other populations (Çag v layan et al, 1994).…”

Haemophilia B mutations in Sweden: a population‐based study of mutational heterogeneity

“…In an early report of the origin of mutations in sporadic cases of haemophilia B, we found that in 6 out of 10 carrier mothers of a sporadic case, the mutation had arisen in the healthy maternal grandfather (Kling et al , 1992), thus implying a higher frequency of mutations in the male than the female X‐chromosome. In a subsample of the Swedish population, Montandon et al (1992) estimated the male to female mutation rate, v/u , to be 11·0. In a recent report, Green et al (1999) have studied a large subsample ( n = 424 families) of the British population and estimated the male to female mutation rate to be 8·64, the female‐specific rate 2·18 and the male‐specific rate 18·82.…”

Analysis of the haemophilia A mutation in sporadic patients registered at the Royal London Hospital and their families

“…It has already been reported that the`int22h' inversions tend to occur in the male germline [15]. Other mutations may also show a bias in favour of male gametic origin as observed in haemophilia B [20,21] but Rossiter et al [22] attribute to the X chromosome an intrinsic tendency to undergo intrachromatid recombination at male meiosis. In keeping with this idea they ®nd no paternal age eect in the origin of these mutations.…”