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Article Dans Une Revue European Journal of Human Genetics Année : 2020

Integrated genome and transcriptome analyses solves about one third of the patients with rare developmental disorders and negative first-line molecular investigations

A. Afenjar
  • Fonction : Auteur

Résumé

Exome sequencing (ES) represents the first-tier diagnostic test in patients presenting with syndromic developmental delay with suspected monogenic etiology. Yet, about 50% of these patients remain unsolved, arguing the interest to extend the genetic investigations beyond the protein-coding genome and to integrate multi-omics approaches. We launched a multi-centric pilot study gathering 53 unsolved patients, after trio ES and array-CGH results, presenting with heterogeneous mild to severe syndromic intellectual disabilities. We performed genome sequencing (GS) combined with transcriptome analysis, highlighting a molecular cause in 32% of the cohort (18/53 patients). GS identified 7 causative structural variants, including 1 deletion, 2 balanced inversions, 1 balanced translocation and 3 complex variants. The molecular readouts of such variants were all validated and furtherly investigated by RNAseq. One deep intronic SNV causing the activation of a cryptic exon, changing the open reading frame of the transcript, was detected by RNAseq. Two frameshift-causing indels were identified in protein-coding regions not captured by ES. Three variants were identified in genes not yet known as disease-causing at the time of the ES analysis. Finally, genotype-phenotype correlation could establish 3 additional diagnoses not identified during the ES analysis. In addition, we detected 2 complex structural variants of unknown significance, not resolvable by short-read GS, as well as new candidate genes identified through RNA-seq differential expression analysis. Overall, GS and RNAseq analyses allowed the identification of the molecular mechanisms underlying 1/3 of previously unsolved patients, and additional candidate variants requiring further investigation (3rd-generation sequencing, 3C techniques) to demonstrate their causality.
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Dates et versions

cea-04419438 , version 1 (26-01-2024)

Identifiants

  • HAL Id : cea-04419438 , version 1

Citer

A. Vitobello, F. T. Mau-Them, A. L. Bruel, Y. Duffourd, E. Tisserant, et al.. Integrated genome and transcriptome analyses solves about one third of the patients with rare developmental disorders and negative first-line molecular investigations. European Journal of Human Genetics, 2020, 28 (Suppl 1), pp.65-66. ⟨cea-04419438⟩
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