XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing

Abstract

Because of the unbalanced sex ratio (1.3-1.4 to 1) observed in intellectual disability (ID) and the identification of large ID-affected families showing X-linked segregation, much attention has been focused on the genetics of X-linked ID (XLID). Mutations causing monogenic XLID have now been reported in over 100 genes, most of which are commonly included in XLID diagnostic gene panels. Nonetheless, the boundary between true mutations and rare non-disease-causing variants often remains elusive. The sequencing of a large number of control X chromosomes, required for avoiding false-positive results, was not systematically possible in the past. Such information is now available thanks to large-scale sequencing projects such as the National Heart, Lung, and Blood (NHLBI) Exome Sequencing Project, which provides variation information on 10,563 X chromosomes from the general population. We used this NHLBI cohort to systematically reassess the implication of 106 genes proposed to be involved in monogenic forms of XLID. We particularly question the implication in XLID of ten of them (AGTR2, MAGT1, ZNF674, SRPX2, ATP6AP2, ARHGEF6, NXF5, ZCCHC12, ZNF41, and ZNF81), in which truncating variants or previously published mutations are observed at a relatively high frequency within this cohort. We also highlight 15 other genes (CCDC22, CLIC2, CNKSR2, FRMPD4, HCFC1, IGBP1, KIAA2022, KLF8, MAOA, NAA10, NLGN3, RPL10, SHROOM4, ZDHHC15, and ZNF261) for which replication studies are warranted. We propose that similar reassessment of reported mutations (and genes) with the use of data from large-scale human exome sequencing would be relevant for a wide range of other genetic diseases.

Figure 1

Representation along the X Chromosome of the 106 Genes in which Mutations Have Been Reported in XLID and Classification According to Both the Type and Number of Mutations Reported in OMIM Genes for which involvement in XLID is convincing are listed on the left side of the chromosome, and genes for which implication in ID either is questionable or needs to be replicated are listed on the right side of the chromosome. GJB1 and MTM1 are linked to diseases with no real ID association and are thus not included in the figure. The color code was designed according to the total number of mutations reported in OMIM. If at least one truncating mutation (splice mutations, nonsense mutations, frameshifts, and large deletions that might encompass several exons) was described, genes are in red (more than five mutations in total), orange (two to five mutations in total), or green (only one mutation). If only missense mutations or mutations involved in expression decrease were identified, genes are in violet (more than five mutations in total), blue (two to five mutations in total), or purple (only one mutation). Asterisks denote genes discussed in this paper but whose implication in ID remains very likely. In parentheses next to each gene are lists in which that gene is included (abbreviations are as follows: L, Lubs; R, Ropers; G, Greenwood Genetic Center; E, Emory Genetics Laboratory; and A, Ambry Genetics). References for the genes not reported in any list are as follows: [1] Honda et al., [2] Houge et al., [3] Voineagu et al., [4] Huang et al., and [5] Witham et al.