Exploring the Genomic Dark Matter of Neurodevelopmental Disorders

SUMMARY Neurodevelopmental disorders (NDDs) comprise of a group of disorders associated with abnormal brain development. NDDs with intellectual disability (ID), characterized by significant limitations in intellectual functioning and adaptive behavior, affect 1% of the population globally and pose a significant public health burden on society. The underlying neuronal mechanisms of dysregulation that trigger NDD onset and progression are not fully understood. Rare genetic variants have been shown to play a key role in their development, especially in those NDDs which are severe in nature. During the last decade, genetic testing has emerged as an important etiological diagnostic test for NDDs with a considerable impact on disease management and treatment. Yet, current genetic testing has a diagnostic rate of ~ 50%. Due to technical limitations in modern next-generation sequencing techniques, these techniques fail to asses a large part of the genome (2/3rd), missing critical regions which may have clinical significance. New methods now have emerged that can assess these regions (i.e. the genomic dark matter) better, can access repetitive regions and identify complex structural genomic events with more accuracy. As such, we hypothesize that a large fraction of genetic variation involved in the etiology of NDDs remains undetected by current sequencing techniques. It is imperative to characterize the spectrum of genomic variants that remain undetected in NDDs to improve diagnostic detection methods. Our goal is two adopt two new cost- effective technologies, i.e. Optical Genome Mapping (OGM) and Single Tube Long Fragment Reads sequencing (stLFR), to identify the underlying genetic cause in 50 genetically unsolved families with severe NDDs including ID. These families were previously investigated using standard short-read sequencing technologies with inconclusive results. Combining both stLFR and OGM will provide an enhanced overview of genomic variation in difficult to diagnose cases, including clinically significant genomic variation. This project is a pilot project aimed to better understand the genomic landscape of variants associated with aberrant neurodevelopment and cognition. Our current understanding of the human genome is still limited due to restrictions in technologies, and these results will lay the foundation for a larger scale study which will eventually improve genetic diagnostic screening and patient management.