%0 Journal Article
%T 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.
%A Colin E
%A Duffourd Y
%A Tisserant E
%A Relator R
%A Bruel AL
%A Tran Mau-Them F
%A Denommé-Pichon AS
%A Safraou H
%A Delanne J
%A Jean-Marçais N
%A Keren B
%A Isidor B
%A Vincent M
%A Mignot C
%A Heron D
%A Afenjar A
%A Heide S
%A Faudet A
%A Charles P
%A Odent S
%A Herenger Y
%A Sorlin A
%A Moutton S
%A Kerkhof J
%A McConkey H
%A Chevarin M
%A Poë C
%A Couturier V
%A Bourgeois V
%A Callier P
%A Boland A
%A Olaso R
%A Philippe C
%A Sadikovic B
%A Thauvin-Robinet C
%A Faivre L
%A Deleuze JF
%A Vitobello A
%J Front Cell Dev Biol
%V 10
%N 0
%D 2022
%M 36393831
%F 6.081
%R 10.3389/fcell.2022.1021785
%X 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.