AUTHOR=Colin Estelle , Duffourd Yannis , Tisserant Emilie , Relator Raissa , Bruel Ange-Line , Tran Mau-Them Frédéric , Denommé-Pichon Anne-Sophie , Safraou Hana , Delanne Julian , Jean-Marçais Nolwenn , Keren Boris , Isidor Bertrand , Vincent Marie , Mignot Cyril , Heron Delphine , Afenjar Alexandra , Heide Solveig , Faudet Anne , Charles Perrine , Odent Sylvie , Herenger Yvan , Sorlin Arthur , Moutton Sébastien , Kerkhof Jennifer , McConkey Haley , Chevarin Martin , Poë Charlotte , Couturier Victor , Bourgeois Valentin , Callier Patrick , Boland Anne , Olaso Robert , Philippe Christophe , Sadikovic Bekim , Thauvin-Robinet Christel , Faivre Laurence , Deleuze Jean-François , Vitobello Antonio
TITLE=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
JOURNAL=Frontiers in Cell and Developmental Biology
VOLUME=10
YEAR=2022
URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.1021785
DOI=10.3389/fcell.2022.1021785
ISSN=2296-634X
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.