CE17 - Recherche translationnelle en santé

Deciphering clinical significance of synonymous Single Nucleotide Variants in neurodevelopmental disorders. – SynoVar

Submission summary

Neurodevelopmental disorders (NDDs) result from anomalies occurring during brain development. Prevalence of NDD is estimated to 1 to 2% of the population worldwide. NDD have an important genetic contribution characterized by an extreme heterogeneity, with more than a thousand of genes identified in monogenic forms so far. Despite the spread use of whole exome sequencing in patients, molecular diagnosis is still lacking for half of the cases, maybe because some variants are misinterpreted.
The SynoVar project propose to revisit the pathogenicity of rare synonymous variants (sSNVs) that have been wrongly considered as silent for the last decades. Owing to the facts that each codon is not translated at the same speed by the ribosome, and that change in local translation rate is deleterious for protein function and stability, sSNVs could be more significant that historically thought. As increasing evidence suggest that many genes identified associated with NDD are sensitive to dosage, sSNVs in these genes could be of clinical relevance by affecting the produced protein amount. By proposing the SynoVar project, we stress that (1) the clinical interpretation of such variants remains extremely challenging, especially for those which affect protein expression without impairing RNA processing, and (2) providing an analytical framework to predict sSNVs that have an impact on translation will resolve a number of NDD diagnostic impasses.
The SynoVar project objective is to characterize pathogenicity of rare synonymous variants in NDD by (1) evaluating the sSNV impact on protein translation using a multi-level approach with and (2) by fine tuning computational methods with appropriate disease-specific experimental measures of tRNA abundance and codon-mediated translational efficiency (TE) to predict sSNVs with pathogenic effects on translation in NDDs. This approach will be unique as it will integrate quantification of tRNA abundance (tRNA-seq data) and TE (Ribo-seq data) in three distinct cell populations (Neuroectodermal cells, neural progenitors and neurons) reflecting the stages of brain development that are affected in NDDs, and, in various human cell lines regularly used in diagnostic labs to provide recommendations for routine functional tests.
The SynoVar project will be developed along four major synergistic research Work Package (WP). WP1 will define a list of sSNVs identified in individuals with NDD and potentially involved in their disease and to select among them the best candidates which will be screened for their potential impacts on protein translation. By generating experimental data from neuronal cells derived from iPSC, WP2 will provide an unprecedented repertoire of TE during human corticogenesis. The WP3 will provide functional validation of the impact on translation of sSNVs in appropriate cellular models and ensure that they do not have impact on mRNA splicing. WP4 will integrate different computational methods to predict for each gene the sSNVs impact on codon optimality using a multi-level approach and cortex-specific experimental data produced in the WP2. It will allow establishing a pathogenicity score for the candidate sSNVs identified in NDD undiagnosed patients (WP1) and identification of the most appropriate cellular model to validate the sSNVs impact in vitro.
Overall, SynoVar will provide a proof of principle that innovative diagnostic tool to estimate the cell-dependent impact of sSNVs on translation is relevant to improve diagnosis of NDD. The ultimate goal to improve the clinical interpretation of sSNVs beyond the splicing defects classically studied, thus offering new diagnostic perspectives. In the long term, this work will help reduce misdiagnosis and improve the management of patients suffering from rare genetic diseases.

Project coordination

Marie DE TAYRAC (Université Rennes 1)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


IGDR Université Rennes 1
IGBMC Centre Européen de Recherche en Biologie et en Médecine
IGBMC Centre Européen de Recherche en Biologie et en Médecine

Help of the ANR 507,061 euros
Beginning and duration of the scientific project: February 2023 - 42 Months

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