Use of Long Read Genome Sequencing in Patients Suffering From Neurodevelopmental Troubles

Patients with neurodevelopmental diseases and their families need to identify the genetic cause of the disease to allow for recognition of the disability, genetic counseling, and possible hope for participation in therapeutic research studies. Access to high-throughput genomic exome or genome analysis allows the identification of a genetic cause for approximately half of the patients. However, families with no result or with a variant of unknown significance after these tests may find themselves in a new diagnostic impasse.The high-throughput sequencing used today generates sequences of the order of 100 base pairs (so-called "short read" sequencing). This allows an analysis of about 90% of the genome. However, many regions are not accessible in regions of interest for the genetic diagnosis of rare diseases. Long fragment sequencing generates sequences that are about 20 times larger and its use has recently made it possible to sequence the human genome almost completely (https://www.science.org/doi/10.1126/science.abj6987). The main contribution lies in the analysis of complex regions of the genome such as segmental duplications or centromeric regions. It is likely that this technology increases the sensitivity of detection of genetic variants in patients with genetic diseases. Its contribution should be studied in patients for whom no genetic cause has been identified by classical techniques.This study aim to investigate the contribution of long fragment genome sequencing.

Inclusion Criteria for patients:Patient (child or adult) presenting neurodevelopmental troubles strongly suspected to suffer from a rare genetic disease (familial or very severe).Negative outcome for short read sequencing of the trio (child and parents).Informed consent to the study by the patient (if applicable) or their legal representatives if under-aged or under guardianship.Patients benefiting from the social security (French health care system).Inclusion criteria for Parents :Possible recruitment of both parents matching the inclusion criteria.Informed consent form signed for their own participation.Parents benefiting from the social security (French health care system).Exclusion Criteria for patients:Genetic predisposition already identified explaining the disease.Paients for which the WGS for the trio has not been performed.Patients having withdrawn their consent.Exclusion Criteria fo Parents :Pregnant or lactating woman.Parents under guardianship or curatorship.Parents also presenting a neurodevelopmental deficiency.