Birth order and the genetics of amyotrophic lateral sclerosis.

The cause of ALS remains largely unknown for the 90% with no known family history, but spontaneous mutation to risk alleles of as yet unidentified genes is possible. It has long been recognized that genetic diseases may be more likely to occur in the last born children of a sibship because increased paternal age is associated with an increased spontaneous point mutation rate in sperm. To test the hypothesis that such a mechanism is responsible for sporadic ALS, we have performed a retrospective analysis of birth order position. We have analyzed sibships of size greater than four using a binomial test for birth position. The 478 pedigrees studied show no birth order effect, suggesting that any genetic contributions to sporadic ALS are more likely to be through deletion in large genes or interactions of common polymorphisms, rather than frequent spontaneous point mutation. This is encouraging for the prospect of finding sporadic ALS susceptibility genes using genome-wide association mapping.