Amidst the fallout of an academic discussion over the worth of GWA studies followed by several gloomy and scathing articles in the popular press, came this paper in Nature Genetics. In summary, the investigators sequenced all the coding DNA on the X-chromosome in families affected with an evidently X-linked mental retardation phenotype. They found nearly 1000 changes that would either alter the amino acid sequence, introduce a frameshift or stop codon, or interfere with splicing, all illustrating the huge heterogeneity problem and the analytical conundrum to face when there are too many potential susceptibility/causal changes. What's more, nearly all of the protein-truncating variants they found were unique to individual families, and many of these were found in both affected and unaffected males! I believe this highlights the fact that an argument pushing for whole-genome sequencing should not omit a discussion of the analytical and interpretation issues we will have to deal with when the time comes.
Nature Genetics: 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.