OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants - Archive ouverte HAL Access content directly
Journal Articles Frontiers in Cell and Developmental Biology Year : 2022

OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

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Nolwenn Jean-Marçais
  • Function : Author
Arthur Sorlin
  • Function : Author
Sébastien Moutton
  • Function : Author

Abstract

Purpose: Patients with rare or ultra-rare genetic diseases, which affect 350 million people worldwide, may experience a diagnostic odyssey. High-throughput sequencing leads to an etiological diagnosis in up to 50% of individuals with heterogeneous neurodevelopmental or malformation disorders. There is a growing interest in additional omics technologies in translational research settings to examine the remaining unsolved cases. Methods: We gathered 30 individuals with malformation syndromes and/or severe neurodevelopmental disorders with negative trio exome sequencing and array comparative genomic hybridization results through a multicenter project. We applied short-read genome sequencing, total RNA sequencing, and DNA methylation analysis, in that order, as complementary translational research tools for a molecular diagnosis. Results: The cohort was mainly composed of pediatric individuals with a median age of 13.7 years (4 years and 6 months to 35 years and 1 month). Genome sequencing alone identified at least one variant with a high level of evidence of pathogenicity in 8/30 individuals (26.7%) and at least a candidate disease-causing variant in 7/30 other individuals (23.3%). RNA-seq data in 23 individuals allowed two additional individuals (8.7%) to be diagnosed, confirming the implication of two pathogenic variants (8.7%), and excluding one candidate variant (4.3%). Finally, DNA methylation analysis confirmed one diagnosis identified by genome sequencing (Kabuki syndrome) and identified an episignature compatible with a BAFopathy in a patient with a clinical diagnosis of Coffin-Siris with negative genome and RNA-seq results in blood. Conclusion: Overall, our integrated genome, transcriptome, and DNA methylation analysis solved 10/30 (33.3%) cases and identified a strong candidate gene in 4/30 (13.3%) of the patients with rare neurodevelopmental disorders and negative exome sequencing results.
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Dates and versions

hal-03886419 , version 1 (06-12-2022)

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Attribution - CC BY 4.0

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Estelle Colin, Yannis Duffourd, Emilie Tisserant, Raissa Relator, Ange-Line Bruel, et al.. OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants. Frontiers in Cell and Developmental Biology, 2022, 10, pp.1021785. ⟨10.3389/fcell.2022.1021785⟩. ⟨hal-03886419⟩
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