A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation

Abstract

Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.

Figure 1

Pedigrees of families with likely deleterious variants in the SYP, ZNF711 and CASK genes. Shaded symbols indicate individuals with mental retardation and open symbols indicate individuals who are unaffected. Symbols containing a red square indicate individuals with both mental retardation and nystagmus. An asterisk indicates the presence of the variant allele and ‘wt’ indicates the presence of the wild-type allele. lod scores are shown in parentheses. (a) SYP. In family MRFU-470, additional individuals were unavailable to genotype. (b) ZNF711. In family 208 the maternal grandfather of the proband (I.1) is thought likely to have mild mental retardation, though this individual was unavailable to enable a detailed clinical assessment. (c) CASK. In family 74, individual III.4 was considered to have milder mental retardation compared to the other affected males and did not present with nystagmus. A lod score of −0.3 was generated when individual III.4 was considered as affected with mental retardation, and a lod score of 1.1 was obtained when his disease status was considered unknown.