It is also plausible that mental retardation in some of the families screened is due to missense variants. Several of the known mental retardation–associated genes initially identified through the presence of truncating changes have disease-causing missense variants reported in other families. Moreover, null alleles due to truncating variants of some X chromosome genes may be lethal in males, whereas missense changes may entail lesser developmental and functional consequences that manifest as mental retardation. However, identification of XLMR genes in which rare, exclusively missense variants are responsible for the disease is challenging. Only a small fraction of missense variants identified in a systematic screen are likely to cause mental retardation. Moreover, judging from the pattern of, mental retardation–causing truncating variants, we predict that they will be distributed over several different genes and that the number in each gene will be small. 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
