Figure 1

Family-based diagnostic strategy for sporadic cases of mental retardation [3]. After excluding de novo pathogenic copy number variations (CNVs) by array CGH analysis and ruling out fragile X syndrome, whole-exome sequencing is performed on the index case and the unaffected parents. A series of bioinformatic filters are used to narrow down the list of candidate mutations. First, mutations deemed to be irrelevant, such as intergenic and synonymous mutations, are removed; common variants are then removed by comparison with genetic variation databases and exome sequencing controls. Finally, inherited variants are removed. The average number of candidate variants after each step in the ten trios investigated by Vissers et al.[3] is shown on the right, and the number next to the dotted arrow indicates the fold reduction of candidates achieved by each step. The final analysis step is performed by means of Sanger sequencing to validate the candidates derived by computational analysis of the WES data.