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COD. C01 Lesson from Exome Analysis of 150 Trios with ASD F COD. C01 Lesson from exome analysis of 150 trios with ASD F. Mari1,2, A. Currò1,2, C. Fallerini1, D. Lopergolo1,2, M. Baldassarri1,2, V. Lamacchia1,2, M.G. Cannone1, S. Croce1, S. Daga1, G. Doddato1, E. Gelli1, A. Giliberti1, E. Lazzarini1, F. Lorenzetti1, M. Palmieri1, S. Amitrano2, M. Bruttini1,2, F.T. Papa1, R. Tita2, C. Lorizzo2, M.A. Mencarelli2, A.M. Pinto2, S. Buoni3, L. Radice2, S. Grosso4, R. Canitano3, F. Ariani1,2, S. De Rubeis5, A. Renieri1,2 1Medical Genetics, University of Siena, Siena, Italy 2Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy 3Child Neuropsychiatry, Azienda Ospedaliera Universitaria Senese, Siena, Italy 4Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy 5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Here, we present data obtained from whole exome sequencing (WES) in 150 patients attending the Medical Genetics Unit of Siena and having a diagnosis of Autism Spectrum Disorders (ASD). All these patients have been evaluated by expert clinicians of our Institution and pathogenic CNVs have been ruled out as the cause of the disease. The project is part of an International effort aiming at identifying the genetic causes of ASD (Autism Sequencing Consortium, Mount Sinai). WES identified the genetic basis of disease in 36% of patients: 14% were already known disease genes and 22% were novel candidates. Among the known genes, SCN2A is recurrently mutated. Interestingly, SCN2A and KCNQ3 mutated patients do not show epilepsy, the key feature of the known associated phenotype. Our data also reinforce the association between SYNGAP1 and PHIP genes with ASD. From a clinical point of view, the identification of PHIP mutations teaches us not to underestimate more common signs such as obesity. PHIP binds the pleckstrin homology domain of insulin receptor substrate-1, a gene modulating insulin signalling and obesity can be a key clinical handle for the diagnosis of PHIP-related neurodevelopmental disorder. More attention has also to be paid to dysmorphology even if no other congenital anomalies are observed. PHIP patients show distinct facial features that can be recognizable such as large ears, thick eyebrows, upturned nose and thin lips. Among the X-linked mutated genes, we confirmed SLC6A8 and PCDH19 as ASD genes in males and females, respectively. Among the new candidates, we identified BCORL1, SLC12A2, CABLES1 and LYPLA2. BCORL1 is expressed in brain and reported mutated in two brothers with severe intellectual disability; SLC12A2 is a Na- K-Cl cotransporter highly expressed in human developing cortical neurons; CABLES1 is a gene required for embryonic neural development and LYPLA2 is a gene needed for axon growth and maintenance differentially expressed in ASD. In conclusion, in our experience, WES analysis has a high success rate in ASD patients. Moreover, these data confirm that ASD is an heterogeneous collection of different rare disorders. Reverse phenotyping in large cohorts will help to better characterize the distinct clinical signs associated to each ASD gene. COD. C02 SINEUP, a modular long non-coding RNA technology as possible new therapeutic tool for haploinsufficiency: CHD8 and CHD2 loss of function mutations in Autism Spectrum Disorders (ASD) and Epilepsy as Proof-of-Principle F. Di Leva 1, M. Arnoldi 1, A. Barbieri 1, G. Alvari1, A. Messina2, M.E. Castellini 2, S. Casarosa2, G.L. Carvill3, S. Zucchelli 4,5, S. Gustincich 4,6, M. Biagioli1 1NeuroEpigenetics lab, Center for Integrative Biology, University of Trento, Trento, Italy 2Neural Development and Regeneration lab, Center for Integrative Biology, University of Trento, Trento, Italy 3Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, USA 4Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), , Trieste, Italy 5Department of Health Sciences, University of Eastern Piedmont 'A. Avogadro', Novara, Italy 6Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), Genova, Italy Autism spectrum disorders (ASD) and epilepsies are heterogeneous conditions that frequently coexist with other developmental disabilities. Genetic basis are prominent risk factors for both disorders and, among others, de novo inactivating mutations in genes of the chromodomain helicase DNA-binding (CHD) family have been reported to be directly causative to the diseases. Specifically, CHD8 represents a recurrent risk factor for ASD, while truncating pathogenic variants in CHD2 lead to epilepsy. CHD proteins function as an ATP-dependent chromatin remodeling factors which can regulate transcription via direct and indirect pathways. We recently mimicked the effects of heterozygous loss-of-function mutations in neural progenitor cells reporting evident alterations in transcriptional regulation, cell proliferation and adhesion. Thus, the sole reduction in CHD8 or CHD2 expression is able to cause cellular and molecular phenotypes that are key hallmarks to follow and rescue in assessing new therapeutic approaches. Particularly, we aim to test SINEUP, a novel class of synthetic long non-coding RNA - recently reported to be able to increase the translation of target proteins to physiological level without affecting transcription - to rescue the phenotypes caused by CHD8 or CHD2 haploinsufficiency.SINEUP activity depends on a binding domain (BD), conferring target specificity and on an effector domain (ED) required for protein translation. By swapping the BD sequence is virtually possible to target any gene of interest. Thus, we firstly designed SINEUP molecules able to recognize the initial and internal methionines of CHD8 and CHD2 proteins. We then proceeded to test the efficacy of different SINEUPs on neural progenitors, in vitro cell system. From our preliminary observations SINEUP targeting internal methionine is more efficient in stimulating CHD8 protein production, thus representing a valid target to be further tested in patients’ derived cell lines and in zebrafish, in vivo model of the disorders.In conclusion, our studies represents the first step towards the development of new types of RNA-based therapy, with implications for a large repertory of presently incurable genetic diseases. COD. C03 CHD8 suppression in neuronal progenitors correlates with alterations in chromatin landscape especially affecting transcriptional initiation and elongation. E. Kerschbamer1, T. Tripathi1, S. Erdin2,3, E. Sebestyen4, F. Di Leva1, M. Benelli5, S. Piazza6, J.F. Gusella2,3, F. Ferrari4, F. Demichelis7, M.E. Talkowski2,3, M. Biagioli1 1Neuro Epigenetics laboratory, Centre for Integrative Biology, University of Trento, Trento, Italy 2Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States 3Department of Neurology, Harvard Medical School, Boston, MA, United States 4Computational genomics laboratory, IFOM, Milan, Italy 5Bioinformatics Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy 6Bioinformatic facility, Centre for Intergrative Biology, University of Trento, Italy 7Laboratory of Computational and Functional Oncology, Centre for Integrative Biology, University of Trento, Trento, Italy Autism Spectrum Disorders (ASD) is a collection of heterogeneous neurodevelopmental disorders defined by social impairment and repetitive behaviors with significant genotypic and phenotypic complexity. Mutations in several hundred loci have been associated with the disease, but the chromodomain helicase DNA binding protein 8 (CHD8) represents a recurrent and independently validated ASD-risk gene. All ASD mutations in CHD8 gene have been reported to be disruptive, leading to haploinsufficiency. Here we investigate how chromatin landscape reacts to CHD8 suppression by analyzing different histone modifications through Chromatin Immunoprecipitation and Sequencing (ChIP-seq) in iPS-derived neural progenitors after CHD8 knock-down. We interrogated transcriptionally active and repressed regions as well as active and poised enhancers to explore the potential impact of loss-of-function mutations.CHD8 suppression mildly affects the overall chromatin landscape leading to a generalized reduction in the number of peaks in actively transcribed (H3K36me3) and enhancer regions (H3K4me1 and H3K27ac). Particularly, transcriptional initiation and elongation chromatin states result the most significantly affected, highlighting genes implicated in “mitotic nuclear division”, “cell cycle” and “mRNA processing” as the major dysregulated targets following CHD8 suppression. Moreover, by overlaying histone marks data with CHD8 binding sites, we observe that most chromatin changes seem to intervene in regions not-bound by CHD8, thus suggesting an ‘indirect mode’ of chromatin remodeling. Although as previously described, CHD8 binds at promoter and enhancer regions, in addition to a general decrease in CHD8 knock-down neural progenitors, H3K36me3 is more enriched in genes bound by CHD8 hinting to a possible connection between the gene-body histone mark and the protein binding at the TSS.Considering the role of H3K36me3 in the regulation of transcription and RNA processing -mainly splicing- we are currently exploring the functional effect of this altered chromatin state at global transcriptomic level. Thus, this study will shed light on possible regulatory mechanisms in the cross-talk between chromatin and transcriptional regulation, possibly relevant to a more
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