The scientific and clinical relevance of studying rare genetic/neurodevelopmental disease

Objective: Intellectual disability (ID) with or without autism spectrum disorders (ASD), is one of the main reasons for referral to a clinical geneticist. ID has a major impact on affected individuals, their families and society. The recent advances in genetic technologies have enabled to identify disease causing variants throughout the whole human exome, even at the single base-pair level of the DNA. This significant increase in diagnostic potential is of high value for proper genetic counseling and paves the way for studying fundamental aspects of brain functioning on one hand and the more personalized approach of syndrome specific management of ID disorders at the clinical site on the other hand. Participants and Methods: So far, over 2000 ID patients have been investigated in our genome diagnostic center by whole exome sequencing which revealed a diagnostic yield of around 30%. Though most genes are very rarely affected, by collaborative efforts with other (inter)national genetic departments, substantial cohorts enable the definition of numerous such novel rare genetic syndromes. Results: Examples of novel syndromes that we have recently defined are GATAD2B, POGZ, KBG, USP9X and DDX3X. The increase in novel syndromes needs multidisciplinary expertise and care including neuropsychiatric involvement. Conclusions: The potential of novel genetic techniques will be discussed and examples of novel syndromes will be given. Syndrome specific management and how to centralize expert knowledge will be highlighted by our experience through our expert center and the formation of European Reference Networks