Delineation of genetic pathomechanisms underlying severe intellectual disability related to Pitt-Hopkins syndrome

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Following our identification of TCF4 haploinsufficiency as the underlying cause for Pitt-Hopkins syndrome, which is associated with severe ID and variable other anomalies, many patients with this suspected diagnosis were referred to our group for TCF4 testing. In various patients without TCF4 mutation, molecular karyotyping enabled us to identify several defects in NRXN1 or CNTNAP2. By utilizing Drosophila melanogaster as a model organism we found indication of a functional interaction between NRXN1 and CNTNAP2. This common molecular basis might provide an explanation for the similar clinical phenotype in the patients. In order to identify further novel genes in our cohort of patients with severe intellectual disability resembling Pitt-Hopkins syndrome, but without mutations in the known genes, we will utilize whole-exome sequencing in trios of patients and their parents. Furthermore, we will continue to use Drosophila melanogaster to functionally characterize the novel genes and investigate molecular interactions between all genes involved. This will help delineate a molecular link as the basis for the phenotypic overlap and to establish a possible starting point for future interventional strategies.