Variability in expression of the 15q11.2 microdeletion syndrome: genetic modifiers in the FMRP network.

The del15q11.2 is associated with intellectual disability, but also with epilepsy, schizophrenia and other neurodevelopmental disorders. Given the importance for genetic counseling, research into the underlying mechanisms of variability in expression is needed. There is increasing evidence that genetic variants in other genes may modify the expression. Therefore, a search for genetic modifiers is expected to yield insight into this variability. With the advent of next generation sequencing technology, the identification of variants in a large number of candidate genes is now possible. However, in order to interpret the wealth of variants, it is essential, in the initial steps, to focus on a limited number of candidate genes, based on an underlying biological relevance. CYFIP1, one of the 4 genes in the del15q11.2, is an attractive candidate for the developmental manifestations. CYFIP1 is part of the FMRP ribonucleoprotein complex, and mutations in FMR1, cause the Fragile-X syndrome. Moreover, the FMRP network is well characterized, allowing to select candidate genes on a biological basis. We will resequence +/- 869 genes from the FMRP network (using exome sequencing) in 40 probands with a familial del15q11.2. Families will be collected in a collaborative study with geneticists from Europe. By analyzing the segregation pattern in the families, we will explore the hypothesis that individuals with a del15q11.2 and ID have an increased burden of pathogenic variants in the FMRP network, and some of them may have occurred de novo. Moreover, we will explore the possibility of mutations occurring in the non-deleted alleles of the four genes in the 15q11.2 region.

Keywords:oligog, intellectual disability, autism

Disciplines:Genetics, Systems biology, Molecular and cell biology