The study highlights, however, some analytical challenges of large-scale, systematic sequencing screens to detect rare disease-causing variants. The extent of genetic heterogeneity can be substantial. Inactivating variants in ~10% of genes on the X chromosome cause XLMR, of which approximately one-third are nonsyndromic. Moreover, individual genes may account for a very small fraction of cases. Mental retardation–causing mutations in SYP and ZNF711 each accounted for only ~0.3% cases, even in a set highly enriched by selection of families compatible with X linkage. Furthermore, disease-causing variants in many XLMR-associated genes constitute only a subset of the rare, nonsynonymous variants that are present. Thus, both SYP and ZNF711 would have been very difficult to detect if most of their disease-causing variants had not been truncating and highly penetrant. Indeed, that we detected them at all in the primary screen of 208 XLMR cases suggests that there are several more XLMR genes that contribute as infrequently.
