American Journal of Medical Genetics 42:213 (1992)
Letter to the Editor Familial Occurrence of Duchenne Dystrophy Through Paternal Lines in Four Families To the Editor:
However, neither of the above calculations applies to the situation described by Zatz et al. 119911.The authors have already ascertained the 454 propositi from the records of their muscular dystrophy program for the years 1969-1988. The question to be asked is thus whether the rate of DMD in relatives of the propositi with DMD, who are connectedthrough males, is greater than that expected by chance. The authors would require accurate infomation about the number of males born in the 454 families, and this information would have to be complete at least as far as the degree of relationship for which positiveDMD are being accepted. For example, in Family 1 the propositi are third cousins and in family 2 they are second cousins Once removed. It would not be unrealistic to expect2550 males per extended family thus providing a denom& nator of (25-50) x 454 or 11,350-22,700 males. The number of cases expected is better calculated on the basis ofthe incidence of DMD, rather than the mutation rate, because the origin ofthe mutations in the secondary is unknown, although 2 mothers are considered to be a t low risk to be carriers. This would provide 3.4 to 6.8 among the 11,350 to 22,700 males. This is not different from what was observed.
Zatz et al. [19911report that in a survey Of454 families ascertained through a propositus with Duchenne muscular dystrophy (DMD) that there were four families with two or more affected males related through the paternal line. Using an estimated mutation rate of 1 x lo4 for DMD they calculate that the probability of two separate mutations in a family is 1 x lo4 x 1 x lo4and conclude that it would “constitute an almost impossible event” to find such an occurrence in 1%oftheir families, and in a population of 31 million People. They go on to propose that in three of their families the explanation lies either in the occurrence of partial deletions, germinal and somatic mosaicism, or the transmission of a transposable element. In the fourth family, where One of the mothers is a proven carrier, they Consider that411 X 1/3q, or a one in 25 X 106event could OCCUr by chance in a population that is currently stated to be 31 million. While these are interesting families, and certainly we must expect the unexpected in genetics these days, 1am concerned that there are errors in the application of the probabilities and that the authors have not allowed for their prior ascertainment of the propositi. REFERENCE One in lo4is the probability of a new mutation at the DMD locus. Therefore lo4 lo4 is the Zatz M, Passos-Bueno MR, Rapaport D, Vainzof M (1991): Familial probability that 2 randomly chosen males from the genoccurrence of Duchenne dystrophy through paternal lines in four families. Am J Med Genet 38:80-84. era1 population will both have DMD. The chance that both the maternal (sibship) and paternal sides of 2 famiAlasdair Hunter lies, again taken at random from the population, would Children’s Hospital of Eastern Ontario both have a male with DMD would be 1 x lo8multiplied Ottawa, Ontario, Canada by the average number of males a t risk-a function of the extent of pedigree data normally gathered.
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Received for publication February 6, 1991. Address reprint requests to Alasdair Hunter, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
0 1992 Wiley-Liss, Inc.