We adopted strategies based on the conservation of the altered amino acid and the number of missense variants in each gene, to highlight missense mental retardation–causing variants. Both of these were productive. However, the discriminative power of such approaches may be limited and the proportion of mental retardation–causing missense variants they have highlighted is unknown. Further study of the remaining missense variants identified here is now indicated. A critical test is whether there is a difference in the prevalence of a putative disease-causing missense variant, or group of variants, between disease cases and controls. However, the size of the sample sets required to investigate this may be daunting for studies of mental retardation and other complex disease phenotypes.
