AbstractRare genetic diseases have been reported with high frequency in some populations. The mechanisms which were proposed to explain most of these observations include founder effect, genetic drift or selective advantage. In recent years, many genes have been sequenced and mutations causing some of these disorders were characterized. According to the analysis of haplotypes and/or mutations, it may be possible to distinguish 3 groups of disorders frequent in isolated populations. In the first group, all the affected patients have only one frequent mutation, suggesting a founder effect with genetic drift. In the second group, more than one mutation is found among the patients; however, most of the patients are homozygotes for one frequent mutation which most probably originated from a common founder; the other patients are compound heterozygotes for the common mutation and a rare mutation. In the third group, more than one frequent mutation is found responsible for each disease. This may be due to a selective advantage which allows the expansion of each new mutation in the particular population or to multiple founder effect with genetic drift in smaller communities which thereafter mixed to form the larger population. © 1994 Wiley‐Liss, I