Optical Mapping for Chromosomal Issues in Neurodevelopmental Disorders

In neurodevelomental disorders, duplications are genomic variations that are difficult to interpret because their orientation cannot be defined by conventional techniques (ACPA and FISH). However, their orientation determines whether a gene disruption and potential loss of function can be validated or not. The same applies to complex chromosomal rearrangements that can involve duplications and deletions, the interpretation of which is made difficult by the limitations of conventional techniques. The Bionano technique is an optical cartography genomic method that will provide access to this information by specifying both balanced and unbalanced chromosomal anomalies, their genomic location, and orientation. Our study is a prospective and multicentric (N=4) study involving 35 patients with neurodevelopmental disorders (NDD) and carrying a chromosomal anomaly identified by chromosomal microarray analysis (ACPA). Depending on the genetic anomaly, patients will be divided into two groups: patients carrying duplications containing or interrupting a gene already implicated in neurodevelopmental disorders. Duplications may involve the X chromosome and be present in male patients. The other group will involve NDD patients with a more complex chromosomal rearrangement (combination of deletion and duplication, ring chromosome structure, combination of multiple genomic imbalances). The optical genomic mapping (OGM) technology developed by Bionano Genomics is an innovative whole-genome exploration technology that enables the identification of balanced or unbalanced structural variants. OGM is based on specific labeling of repetitive regions following extraction of high molecular weight DNA (fragments ranging from 100kb to 2Mb). The algorithms associated with this new technology allow the identification of balanced structural rearrangements as small as 500bp and unbalanced rearrangements as small as 5kb. This technique also enables the physical localization of each analyzed region, characterizing insertions, deletions, duplications, repeat expansions, inversions, and translocations. Finally, in the first group, this technology is expected to allow us to characterize the breakpoints and orientation of duplicated segments in order to better understand the functional impact on the interrupted gene. Indeed, duplication can result in obtaining a complete additional copy of the gene, disrupt the gene leading to its misregulation (equivalent to a loss-of-function variation), disrupt another gene if the duplicated segment is inserted elsewhere in the genome or if it involves a regulatory region, or have no effect on gene expression. Similarly, in the second group, this technique will allow us to characterize the complex chromosomal rearrangement at the molecular level and define its functional impact. This technology will enable us to better understand the pathophysiology of pediatric neurodevelopmental disorders (NDD) and guide the genetic counseling provided to the patient and their family. Furthermore, more generally, the results will help us better understand the complex architecture of neurodevelopmental disorders, ultimately allowing for more targeted therapeutic solutions. Finally, our study will assess the contribution of this technique and its feasibility in routine clinical practice.