A CELL REPROGRAMMING-BASED APPROACH TO STUDY 7Q11.23 GENE DOSAGE IMBALANCES IN WILLIAMS BEUREN SYNDROME AND AUTISM SPECTRUM DISORDER

Symmetrical gene dosage imbalances at 7q11.23 chromosomal region cause two unique neurodevelopmental diseases, Williams Beuren Syndrome (WBS) and the 7q11.23 microduplication associated to autistic spectrum disorder (7dup-ASD). Although both these diseases share common features such as intellectual disability and craniofacial dysmorphism, they can be distinguished by distinct social and language abilities: WBS patients characterized by hypersociality and comparatively well-preserved language skills while 7dup-ASD is associated with impairment in social interaction and communicative skills. The involvement of same genetic interval in these disease, points out to small subset of dosage-sensitive genes affecting cognition, social behavior and communication skills. Among the genes in the deleted region, some were shown to contribute to the abnormalities in these patients through transgenic mice models and individual case reports. However, the precise cellular and molecular phenotypes associated with these syndromes in disease-relevant cell-types are unknown due to the scarce availability of primary diseased tissues. Transcription factor induced somatic cell reprogramming has bypassed such fundamental limitation and has enabled us to model human diseases, elucidate their pathogenesis and discover new therapeutics by screening small chemicals/drugs on these models. During my PhD studies, I focused on the functional dissection of these complementary diseases at the level of transcriptional deregulation in patient-derived iPSC and its differentiated derivatives such as neural crest stem cells, mesenchymal stem cells, and neural progenitors. To this end, we have assembled a unique cohort of typical WBS, atypical WBS (patient with a partial deletion) and 7dup-ASD patients (along with unaffected relatives), and then I used mRNA reprogramming to establish and characterize at least 3 independent iPSC lines from a total of 12 individuals. High throughput mRNA sequencing on iPSC revealed critical transcriptional derangements in disease-relevant pathways already at the pluripotent state. These alterations found to be selectively amplified upon differentiation into disease-relevant lineages, thereby establishing the value of large iPSC cohorts in the elucidation of disease-relevant developmental pathways. Finally, we created an open-access web-based platform to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes.