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Journal Articles Journal of Medical Genetics Year : 2019

Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders

Caroline Schluth-Bolard
Flavie Diguet
  • Function : Author
Nicolas Chatron
  • Function : Author
Pierre-Antoine Rollat-Farnier
  • Function : Author
Alexandra Afenjar
  • Function : Author
Florence Amblard
  • Function : Author
Jeanne Amiel
  • Function : Author
Sophie Blesson
  • Function : Author
Patrick Callier
Yline Capri
  • Function : Author
Patrick Collignon
  • Function : Author
Marie-Pierre Cordier
  • Function : Author
Christine Coubes
  • Function : Author
Benedicte Demeer
Annabelle Chaussenot
  • Function : Author
Florence Demurger
  • Function : Author
Françoise Devillard
  • Function : Author
Martine Doco-Fenzy
Céline Dupont
Jean-Michel Dupont
  • Function : Author
Sophie Dupuis-Girod
  • Function : Author
Laurence Faivre
  • Function : Author
Brigitte Gilbert-Dussardier
  • Function : Author
Anne-Marie Guerrot
  • Function : Author
Marine Houlier
  • Function : Author
Bertrand Isidor
  • Function : Author
Sylvie Jaillard
  • Function : Author
Géraldine Joly-Hélas
  • Function : Author
Valérie Kremer
  • Function : Author
Didier Lacombe
  • Function : Author
Cédric Le Caignec
  • Function : Author
Aziza Lebbar
  • Function : Author
Marine Lebrun
  • Function : Author
Gaetan Lesca
  • Function : Author
James Lespinasse
  • Function : Author
Jonathan Levy
  • Function : Author
Valérie Malan
  • Function : Author
Michele Mathieu-Dramard
  • Function : Author
Julie Masson
  • Function : Author
Alice Masurel-Paulet
  • Function : Author
Cyril Mignot
  • Function : Author
Chantal Missirian
  • Function : Author
Fanny Morice-Picard
  • Function : Author
Sébastien Moutton
  • Function : Author
Gwenaël Nadeau
  • Function : Author
Céline Pebrel-Richard
  • Function : Author
Sylvie Odent
  • Function : Author
Véronique Paquis-Flucklinger
  • Function : Author
Laurent Pasquier
  • Function : Author
Nicole Philip
  • Function : Author
Morgane Plutino
  • Function : Author
Linda Pons
  • Function : Author
Marie-France Portnoï
  • Function : Author
Fabienne Prieur
  • Function : Author
Jacques Puechberty
  • Function : Author
Audrey Putoux
  • Function : Author
Marlène Rio
  • Function : Author
Caroline Rooryck-Thambo
  • Function : Author
Massimiliano Rossi
  • Function : Author
Catherine Sarret
  • Function : Author
Véronique Satre
  • Function : Author
Jean-Pierre Siffroi
  • Function : Author
Marianne Till
  • Function : Author
Renaud Touraine
  • Function : Author
Annick Toutain
  • Function : Author
Jérome Toutain
  • Function : Author
Stéphanie Valence
  • Function : Author
Alain Verloes
  • Function : Author
Sandra Whalen
  • Function : Author
Patrick Edery
Anne-Claude Tabet
  • Function : Author
Damien Sanlaville
  • Function : Author

Abstract

Background Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. Methods Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. Results Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption ( KANSL1 , FOXP1 , SPRED1 , TLK2 , MBD5 , DMD , AUTS2 , MEIS2 , MEF2C , NRXN1 , NFIX , SYNGAP1, GHR, ZMIZ1 ) and 7 by position effect ( DLX5 , MEF2C , BCL11B , SATB2, ZMIZ1 ). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. Conclusion Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

Dates and versions

hal-04383078 , version 1 (09-01-2024)

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Caroline Schluth-Bolard, Flavie Diguet, Nicolas Chatron, Pierre-Antoine Rollat-Farnier, Claire Bardel, et al.. Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders. Journal of Medical Genetics, 2019, 56 (8), pp.526-535. ⟨10.1136/jmedgenet-2018-105778⟩. ⟨hal-04383078⟩
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