Abstract
Intellectual disability (ID) affects 1-3% of the population. A genetic origin is estimated to account for about half of the currently undiagnosed cases, and despite recent successes in identifying some of the genes, it has been suggested that hundreds more genes remain to be identified. ID can be isolated or part of a more complex clinical picture –indeed other symptoms are often found in patients with severe genetic ID, such as developmental delay, organ malformations or seizures.
In this project, we used whole exome sequencing (WES) to analyse the coding regions of the genes (exons) of patients with undiagnosed ID and that of their families. The variants called by our algorithm were then grossly sorted out using criteria such as frequency in the general population and predicted pathogenicity. A second round of selection was made by looking at the relevant literature about the function of the underlying genes and pathways involved. The selected variants were then Sanger-sequenced for confirmation. This strategy allowed us to find the causative variant and give a diagnosis to the first family we analysed, as the patient was carrying a mutation in the Methyl-CpG binding protein 2 gene (MECP2), already known to cause Rett syndrome. For the second family we could not elucidate the cause of ID with certainty. We have a suspicion that a variant in the Synaptotagmin-Like 2 gene (SYTL2) may be the cause of the symptoms, but we could not prove it as no other patients harbouring this variant and similar clinical traits have been found up to now. However SYTL2 remains our strongest candidate as it is involved in a pathway known to cause ID and because SYTL3 was recently uncovered as a cause of ID in Pr Reymond’s lab (unpublished data). A first step forward would be to perform functional studies to confirm the protein-disrupting nature of the variant.