Decoding Developmental Disorders in Humams

Developmental disorders, which encompass congenital anomalies and intellectual disabilities - including autism spectrum disorders - constitute a vast group of pathologies, caused by a complex set of genetic and environmental factors. They can affect several organs or tissues, such as brain abnormalities, head and neck malformations, heart defects, skeletal disorders and ophthalmological or hearing pathologies. They occur in around 2-3% of live births - affecting around 150,000 newborns every year in Europe (1). These pathologies are associated with high morbidity and mortality rates. They were responsible for 632,000 deaths worldwide in 2013 (2), representing a major social, economic and health problem. Together, these diseases represent a considerable challenge in terms of medical care and genetic counseling, underlining the major deficits in fundamental and clinical knowledge to date. At the Hôpital Necker-Enfants malades and the Institut des Maladies Génétiques Imagine, between 20,000 and 25,000 patients suffering from a wide range of developmental disorders are treated every year. Multidisciplinary consultations, together with state-of-the-art genomic investigations such as comparative genome hybridization (CGH) and whole exome sequencing (WES), provide the research and clinical teams involved with in-depth knowledge of the natural history of these diseases and the phenotypes of affected patients, as well as a better understanding of their genetic basis. Despite this, the rate of unknown diagnoses is very high (over 65-70% of cases remain without a distinct pathophysiological label), due to both the heterogeneity of these diseases and the complexity of their genetic architecture, probably involving non-coding DNA in many cases. Studying this non-coding DNA therefore requires technologies such as whole genome sequencing (WGS). The main aim of the DEVO-DECODE project is to align our currently limited knowledge of the genetic architecture of developmental disorders with our more advanced knowledge of their "phenome". To meet this challenge,we propose to draw on the expertise and resources available within the research and clinical teams at Institut Imagine and Hôpital Necker, in order to: 1. create well-characterized, homogeneous cohorts. 2. systematize the collection of samples from patient care for biobanking and other studies. 3. carry out WGS studies not only to refine exome sequencing data, but above all to identify and validate non-coding DNA alterations, in both transcribed and non-transcribed genomic domains. 4. develop precise preclinical models for functional studies of candidate pathophysiological pathways.