Advances in technology and knowledge in the field of Genomics provide new exciting opportunities in the context of Precision Medicine. Nowadays it is possible to sequence human genomes with high-throughput e and low costs. In addition the genetic basis and pathogenic mechanismsm underlying many diseases has been revealed, particularly in the field of pediatrics. In this context, new medical needs and scientific questions can be challenged, such as the implementation of genomics into diagnostic workflows for personalized clinical management, the development of innovative therapies based on molecular information, the detection of causative mutations for ultrarare undiagnosed syndromes, the identification of genetic risk factors for common multifactorial diseases, the biological role of noncoding transcribed or untranscribed genomic sequences. The challenge of Genomics require a multidiscipinary approach involving diverse expertises in the field of medicine, biology, informatics and statistics and the implementation of advanced technological platforms for generation, analysis and interpretation of large amount of data. Institute Gaslini and Italian Institute of Genomics have recently identified Genomics as strategic area of cooperation in the context of their specific mission in Healthcare and Life Sciences. Based on and diverse and synergic expertises the Institutes launched in April 2018 a Joint lab on Genomics. IIT will bring to the common project the most advanced technological platforms for sequencing of nucleic acids and powerful computational know-how and resources for analysis of biomedical data. Institute Gaslini will contribute deep phenotyped populations and provide unique expertise for genotype-phenotype correlations. The main objective of the project is to bring the recently created GAslini-IIT Joint Lab of Genomics to full operativity. Toward this objective we propose the following specific aims: Aim 1) To implement advanced protocols for nucleic acid sequencing and bioinformatic pipelines to generate high-quality, high-throughput genomic sequences and at low costs. GIGA will initially use a Novaseq Illumina Platform for short reads sequencing and a HPC facility. During the course of the project the center will evaluate a platform for long reads sequencing. Aim 2) To organize a clinical database for deep phenotyping based on Human Phenome Ontology (HP) terms and a genotype reference database based on OPenCGA platform to allow a bioinformatic approach to genotype-phenotype correlations. For this purpose we will establish a Clinical Board for selection and phenotyping of patients. Aim 3) To translate genome or exome sequecing into the diagnostic workflow of diverse areas of pediatrics. Current genetic tests rely on different multi-gene panels. This approach has major limitations: does not dynamically capture new knowledge from research, does not allow a unique standardized sequencing procedure and has limited sensitivity for many unclassified conditions. We will overcome this approach by systematically performing exome sequencing and dynamically tuned bioinformatic analysis according to each specific phenotype. We will cover many areas of pediatrics with a particular focus on neurological, muscular, immunological, renal diseases and in complex congenital disorders. In parallel, we will also explore the feasibility of introducing genome sequencing into the diagnostic workflow. We will also focus to establish procedures for cyclic re-analysis of data according to the availability of new emerging knowledge. Aim 4) To uncover the genetic basis of different diseases. We designed the following subprojects according to emerging medical needs and available expertise. i) identification of novel genes for ultrare syndromic conditions; ii) detection of risk factors for common neuropsychiatric disorders including autistic spectrum disorders, intellectual disability and epilepsy, with a specific focus on noncoding repetitive elements; iii) genetic profiling of specific disease populations for personalized therapies (e.g. immunodeficiencies) The main outcome of the project is the full operativity of the Joint Genomic Lab. Specific aims were defined to establish protocols, procedures and resources (aims 1 and 2), to ensure a significant translational impact on healthcare (aim 3) and to generate new knowledge in specific fields of pediatric medicine (aim 4). The Joint Lab will be open to many other regional, national and international projects, when it will reach full operativity. In addition the new knowledge generated by the project may open new opportunities such as identification of molecular targets or mechanisms for innovative therapies, personalized rehabilitative approaches for neurodevlopmenal disorders through robotic devices. In addition, genomics may be complemented by other Omics such as metabolomic and proteomics toward a high-density molecular phenotyping of patients. At the end of the project we aim to implement a Genomic approach to genetic disease. This model will be applied to Pediatric disorders where genetics plays a pivotal role. However the model may be eventually extended to adult hospital. Literature data indicate that genomic approaches allows molecular diagnosis in about 40% of undiagnosed cases. Our goal is to sequence at least 1.000 genomes/exomes in the 24 months of the project. Accordingly, we expect to achieve a diagnosis in about 400 cases with a significant benefit in clinical management. The full operativity of the Joint Lab will ensure sustainable, efficient and sensitive 3rd generation genetic testing for the many patients referred to Institute Gaslini in the years to come.