Of the 19 genes with truncating variants in controls and/or in which the truncating variant does not segregate with mental retardation, eight (40%) have only a single exon, compared to 10% (73/718) of X-chromosome genes screened overall (P = 0.004). The enrichment in single-exon structures suggests that some may be retrotransposed copies that are being progressively excluded from the human genome by acquisition of truncating variants32,33. For UBE2NL and RPL9P7 the presence of a multiexon copy with very high sequence identity elsewhere in the genome provides evidence in favor of this hypothesis. However, other genes (ARSF, BEX4, DRP2, MAP3K15, MAP7D3, SAGE1, SATL1, SSX6, SYTL5, USP9X, VSIG4 and ITIH5L) have multiple exons. In the case of ARSF, there may be functional redundancy through closely related arylsulfatase genes elsewhere in the genome. In principle, it is possible that the deleterious effects of some of these truncating variants may be averted by transcript processing. The results overall, however, indicate that >1% of the currently defined protein-coding gene set on the X chromosome are not required for normal existence and cognitive function in humans.
