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
2022
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
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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