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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

Authors :
Estelle Colin
Yannis Duffourd
Emilie Tisserant
Raissa Relator
Ange-Line Bruel
Frédéric Tran Mau-Them
Anne-Sophie Denommé-Pichon
Hana Safraou
Julian Delanne
Nolwenn Jean-Marçais
Boris Keren
Bertrand Isidor
Marie Vincent
Cyril Mignot
Delphine Heron
Alexandra Afenjar
Solveig Heide
Anne Faudet
Perrine Charles
Sylvie Odent
Yvan Herenger
Arthur Sorlin
Sébastien Moutton
Jennifer Kerkhof
Haley McConkey
Martin Chevarin
Charlotte Poë
Victor Couturier
Valentin Bourgeois
Patrick Callier
Anne Boland
Robert Olaso
Christophe Philippe
Bekim Sadikovic
Christel Thauvin-Robinet
Laurence Faivre
Jean-François Deleuze
Antonio Vitobello
Source :
Frontiers in Cell and Developmental Biology, Vol 10 (2022)
Publication Year :
2022
Publisher :
Frontiers Media S.A., 2022.

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.

Details

Language :
English
ISSN :
2296634X
Volume :
10
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cell and Developmental Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.232e817b8e4d02a082ed5b52095a4f
Document Type :
article
Full Text :
https://doi.org/10.3389/fcell.2022.1021785