Developmental disorders

Stéphane Bézieau

Our team has made a very significant contribution to the identification of new genes responsible for rare diseases, particularly ID, in recent years. These discoveries were made possible through the recruitment of patients by consultations at the medical genetics department and the high level of expertise in high-throughput genomic analysis.

The starting point was the coordination of a Hospital Clinical Research Project (PHRC) called HUGODIMS (Interregional Project of the Great West of France for the Exploration by Exome Approach of Molecular Causes of Moderate or Severe Intellectual Disability. Seventy-six patients with moderate to severe isolated or syndromic ID were included, in six hospitals, during genetic consultations performed over a 6-month period in 2014. These patients had been selected on clinical criteria and obviously after exclusion of Fragile X syndrome, or abnormalities observed by karyotype, or by Comparative genomic hybridization. The strategy implemented was the sequencing of exome trios (parental DNA was also sequenced) in order to facilitate the interpretation of data for the identification of new genes, thanks to the expected de novo status of a large number of mutations. This PHRC yielded a 40% diagnostic rate within the cohort, which is much higher than the 14% rate of molecular abnormalities found by sequencing the 44 main genes known in ID.

At the research level, this work allowed the identification of new candidate genes in 20% of the ID cases. In addition, this work has prompted very successful international collaborations, notably with Baylor College of Medicine, to assemble cohorts of patients with the same rare disease caused by mutations in the same gene. Likewise, a collaboration with the Zebrafish modeling laboratory (Duke University) provided insight into the pathogenicity of the variants by showing their impact in mutant fishes. This collaborative strategy led to about 20 high-level international publications (2016–2018), while several others are currently being reviewed (e.g., a manuscript by Cogné et al. reviewed favorably by the American Journal of Human Genetics) (or in preparation Latypova et al.). Given the results obtained in the first HUGODIMS series, additional funds were allocated to our team for the sequencing of 80 additional trios. The HUGODIMS 2 project is currently in progress. At the same time, the Fondation Maladies Rares [French Foundation for Rare Diseases] has funded sequencing by the genome-trios approach for about twenty patients whose cause of disorder could not be explained by exome trio analysis. The first data (unpublished) have yielded promising results, with the identification of four molecular causes out of seven trios analyzed to date.

• ANR UPS-NDDecipher - Sébastien Küry (2022-2025)

Ebstein F, Küry S, Most V, Rosenfelt C, Scott-Boyer M-P, van Woerden GM, et al.
PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production.
Sci Transl Med 2023;15:eabo3189.

Küry S et al.
De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.
Am J Hum Genet 100: 352–363, 2017.

Guissart C, et al.
Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.
Am J Hum Genet 102: 744–759, 2018.

Funding

• ANR
• AXA
• FHU HUGO
• Région Pays de la Loire