Integrated genome and transcriptome analyses solves about one third of the patients with rare developmental disorders and negative first-line molecular investigations
A. Vitobello
(1, 2)
,
F. T. Mau-Them
(1, 2)
,
A. L. Bruel
(1, 2)
,
Y. Duffourd
(1)
,
E. Tisserant
(1)
,
P. Callier
(1, 2)
,
S. Moutton
(1, 3)
,
S. Nambot
(1, 3)
,
D. Lehalle
(1, 3)
,
N. Jean-Marcais
(3)
,
J. Delanne
(1, 3)
,
C. Racine
(1)
,
J. Thevenon
(3)
,
C. Poe
(1)
,
T. Jouan
(1)
,
M. Chevarin
(1)
,
M. Willems
(4)
,
C. Coubes
(4)
,
D. Genevieve
(4, 5)
,
N. Houcinat
(3, 1)
,
A. Masurel-Paulet
(3)
,
A. Mosca-Boidron
(1, 2)
,
A. Sorlin
(1, 2, 3)
,
Bertrand Isidor
(6)
,
S. Heide
(7)
,
A. Afenjar
(8)
,
D. Rodriguez
(8, 9)
,
C. Mignot
(7)
,
D. Heron
(7)
,
M. Vincent
(6)
,
P. Charles
(7)
,
S. Odent
(10, 11)
,
C. Dubourg
(12)
,
A. Faudet
(7)
,
B. Keren
(7)
,
Benjamin Cogné
(13)
,
Anne Boland
(14)
,
Robert Olaso
(14)
,
C. Philippe
(1, 2)
,
Jean-François Deleuze
(14)
,
L. Faivre
(1, 3)
,
C. Thauvin-Robinet
(1, 3)
1
LNC -
Lipides - Nutrition - Cancer [Dijon - U1231]
2 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
3 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
4 Département de génétique médicale, maladies rares et médecine personnalisée [CHU Montpellier]
5 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
6 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
7 CHU Pitié-Salpêtrière [AP-HP]
8 CHU Trousseau [APHP]
9 SU - Sorbonne Université
10 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
11 IGDR - Institut de Génétique et Développement de Rennes
12 Service de Génétique moléculaire et Génomique [CHU Rennes]
13 ITX - ITX - unité de recherche de l'institut du thorax
14 CNRGH - Centre National de Recherche en Génomique Humaine
2 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
3 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
4 Département de génétique médicale, maladies rares et médecine personnalisée [CHU Montpellier]
5 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
6 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
7 CHU Pitié-Salpêtrière [AP-HP]
8 CHU Trousseau [APHP]
9 SU - Sorbonne Université
10 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
11 IGDR - Institut de Génétique et Développement de Rennes
12 Service de Génétique moléculaire et Génomique [CHU Rennes]
13 ITX - ITX - unité de recherche de l'institut du thorax
14 CNRGH - Centre National de Recherche en Génomique Humaine
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.