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

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.

Survey of the Landscape of Society Practice Guidelines for Genetic Testing of Neurodevelopmental Disorders

“…While it may seem intuitive that ES/WGS would report more variants of unknown significance (VUS) compared to multi-gene panels, the opposite has been reported, likely reflective of higher rates of concurrent parental sample availability and higher phenotypic correlation required for generating ES/WGS reports 34 . Beyond ES/WGS, evidence supporting the clinical utility of newer technologies such as long-read WGS, transcriptomics, polygenic risk scores, and epigenetic profiling is emerging [35][36][37][38] . Without regularly updated, comprehensive clinical genetic testing guidelines accepted by multiple specialties that care for NDD patients, patients may receive less effective, less comprehensive testing, leading to missed opportunities for genetic diagnoses and the associated benefits.…”

Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders

“…By integrating short-read genome sequencing, transcriptomics, and epigenomics (DNA methylation) analyses, we resolved about 33% of the patients with heterogeneous rare neuro-developmental disorders with previous negative exome sequencing results. We also identified 13% additional candidate variants (Colin et al, 2022). This approach is effective in identifying causative variants when exhaustive clinical information is available for genotype-phenotype correlation analysis.…”

The Genetics of Intellectual Disability

“…The use of transcriptomics in patients in whom exome interpretation alone did not identify the genetic cause yielded an additional 10-35% diagnoses. The first systematic transcriptomes for patients with neurodevelopmental disorders have also booked their first successes as was recently shown by analyzing 30 patients and obtaining a conclusive diagnosis in 27% [116]. The next challenge in the use of transcriptomics will be the upgrade from short-read sequencing technologies to long-read technologies (IsoSeq), allowing the interrogation of full native transcripts [117] as well as single cell transcriptomics [118].…”