Identification of mobile retrocopies during genetic testing: Consequences for routine diagnosis

Nicolas Chatron (1, 2) , Kevin Cassinari (3) , Olivier Quenez (3) , Stéphanie Baert‐desurmont (3) , Claire Bardel (4, 5) , Marie‐pierre Buisine (6) , Eduardo Calpena (7) , Yline Capri (8) , Jordi Corominas Galbany (9) , Flavie Diguet , Patrick Edery (10) , Bertrand Isidor (11) , Audrey Labalme (10) , Cedric Le Caignec (11) , Jonathan Levy (12) , François Lecoquierre (3) , Pierre Lindenbaum (13) , Olivier Pichon (14) , Pierre‐antoine Rollat‐farnier , Thomas Simonet (2) , Pascale Saugier‐veber (3) , Anne‐claude Tabet (15, 16) , Annick Toutain (17, 18) , Andrew Wilkie , Gaetan Lesca (4) , Damien Sanlaville (1) , Gaël Nicolas (19, 3) , Caroline Schluth‐bolard (2, 1)

1 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
2 HCL - Hospices Civils de Lyon
3 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
4 GHE - Groupement Hospitalier Lyon-Est
5 Service de Biostatistiques [Lyon]
6 LilNCog - Lille Neurosciences & Cognition - U 1172
7 University of Oxford
8 Département de génétique [Robert Debré]
9 Radboud University Medical Center [Nijmegen]
10 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
11 Service de génétique médicale - Unité de génétique clinique [Nantes]
12 Hôpital Robert Debré
13 ITX - ITX - unité de recherche de l'institut du thorax
14 Gatonero SA
15 AP-HP Hôpital universitaire Robert-Debré [Paris]
16 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
17 Service de génétique [Tours]
18 iBraiN - Imaging, Brain & Neuropsychiatry
19 GMFC - Génétique du cancer et des maladies neuropsychiatriques

Human retrocopies, that is messenger RNA transcripts benefitting from the long interspersed element 1 machinery for retrotransposition, may have specific consequences for genomic testing. Next genetration sequencing (NGS) techniques allow the detection of such mobile elements but they may be misinterpreted as genomic duplications or be totally overlooked. We report eight observations of retrocopies detected during diagnostic NGS analyses of targeted gene panels, exome, or genome sequencing. For seven cases, while an exons-only copy number gain was called, read alignment inspection revealed a depth of coverage shift at every exon-intron junction where indels were also systematically called. Moreover, aberrant chimeric read pairs spanned entire introns or were paired with another locus for terminal exons. The 8th retrocopy was present in the reference genome and thus showed a normal NGS profile. We emphasize the existence of retrocopies and strategies to accurately detect them at a glance during genetic testing and discuss pitfalls for genetic testing.

Mots clés: copy number gain; genetic testing pitfalls; genome mobility; retrocopies

Domaines: Génétique

Nicolas Chatron, Kevin Cassinari, Olivier Quenez, Stéphanie Baert‐desurmont, Claire Bardel, et al.. Identification of mobile retrocopies during genetic testing: Consequences for routine diagnosis. Human Mutation, 2019, 40 (11), pp.1993-2000. ⟨10.1002/humu.23845⟩. ⟨hal-02339267⟩