Frequency of new mutants among boys with Duchenne muscular dystrophy

Haldane's rule states that one-third of the cases of an X-linked recessive lethal should represent new mutations. This rule is derived under the assumptions that there is equilibrium between mutation and selection, that mutation rates in ova and sperm are equal, and that heterozygous and homozygous normal women have the same fitness. To test this rule for Duchenne muscular dystrophy (DMD), we have examined the mothers of 55 boys with DMD (16 familial and 39 isolated cases) and classified them as carriers or noncarriers on the basis of measures of ribosomal protein synthesis (RPS). Of the 55 mothers, only nine (16.4%) are classified as noncarriers, a figure significantly different from the expected one-third. When the analysis is limited to the 39 mothers of isolated cases, 23.1% (9/39) are classified as noncarriers, still significantly different than expected under Haldane's rule. Violation of any of the assumptions under which Haldane's rule is derived could lead to deviations from the expected one-third new mutants. We find the most likely explantation to be a higher male than female mutation rate. This is supported also by the finding that maternal grandfathers in whom a mutation occurred had higher mean age at birth of the carrier daughter (33.7 +/- 1.6) than did the general population or intrapedigree controls (29.5 +/- 1.3).