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

在我们确定TCF4单倍功能不全是皮特-霍普金斯综合征的潜在原因之后，许多有这种疑似诊断的患者被转到我们组进行TCF4检测。在各种没有TCF4突变的患者中，分子核型使我们能够识别NRXN1或CNTNAP2的几个缺陷。通过使用黑腹果蝇作为模式生物，我们发现NRXN1和CNTNAP2之间存在功能相互作用的迹象。这种共同的分子基础可能为患者相似的临床表型提供了解释。为了在我们的严重智力残疾患者队列中进一步识别新的基因，类似于皮特-霍普金斯综合征，但没有已知基因突变，我们将对患者及其父母的三人组进行全外显子组测序。此外，我们将继续使用果蝇对新基因进行功能表征，并研究所有相关基因之间的分子相互作用。这将有助于描述作为表型重叠基础的分子联系，并为未来的干预策略建立一个可能的起点。

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.