Frontiers in Cell and Developmental Biology (Oct 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

  • Estelle Colin,
  • Estelle Colin,
  • Yannis Duffourd,
  • Yannis Duffourd,
  • Emilie Tisserant,
  • Raissa Relator,
  • Ange-Line Bruel,
  • Ange-Line Bruel,
  • Frédéric Tran Mau-Them,
  • Frédéric Tran Mau-Them,
  • Anne-Sophie Denommé-Pichon,
  • Anne-Sophie Denommé-Pichon,
  • Hana Safraou,
  • Hana Safraou,
  • Julian Delanne,
  • Julian Delanne,
  • Nolwenn Jean-Marçais,
  • Boris Keren,
  • Bertrand Isidor,
  • Marie Vincent,
  • Cyril Mignot,
  • Cyril Mignot,
  • Delphine Heron,
  • Alexandra Afenjar,
  • Solveig Heide,
  • Anne Faudet,
  • Perrine Charles,
  • Sylvie Odent,
  • Sylvie Odent,
  • Yvan Herenger,
  • Arthur Sorlin,
  • Sébastien Moutton,
  • Jennifer Kerkhof,
  • Haley McConkey,
  • Martin Chevarin,
  • Martin Chevarin,
  • Charlotte Poë,
  • Charlotte Poë,
  • Victor Couturier,
  • Victor Couturier,
  • Valentin Bourgeois,
  • Valentin Bourgeois,
  • Patrick Callier,
  • Anne Boland,
  • Robert Olaso,
  • Robert Olaso,
  • Christophe Philippe,
  • Christophe Philippe,
  • Bekim Sadikovic,
  • Bekim Sadikovic,
  • Christel Thauvin-Robinet,
  • Christel Thauvin-Robinet,
  • Christel Thauvin-Robinet,
  • Laurence Faivre,
  • Laurence Faivre,
  • Jean-François Deleuze,
  • Jean-François Deleuze,
  • Antonio Vitobello,
  • Antonio Vitobello

DOI
https://doi.org/10.3389/fcell.2022.1021785
Journal volume & issue
Vol. 10

Abstract

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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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