Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders
Authors: Schluth-Bolard Caroline , Diguet Flavie , Chatron Nicolas , Rollat-Farnier Pierre-Antoine , Bardel Claire , Afenjar Alexandra , Amblard Florence , Amiel Jeanne , Blesson Sophie , Callier Patrick , Capri Yline , Collignon Patrick , Cordier Marie-Pierre , Coubes Christine , Demeer Benedicte , Chaussenot Annabelle , Demurger Florence , Devillard Françoise , Doco-Fenzy Martine , Dupont Céline , Dupont Jean-Michel , Dupuis-Girod Sophie , Faivre Laurence , Gilbert-Dussardier Brigitte , Guerrot Anne-Marie , Houlier Marine , Isidor Bertrand , Jaillard Sylvie , Joly-Hélas Géraldine , Kremer Valérie , Lacombe Didier , Le Caignec Cédric , Lebbar Aziza , Lebrun Marine , Lesca Gaetan , Lespinasse James , Levy Jonathan , Malan Valérie , Mathieu-Dramard Michele , Masson Julie , Masurel-Paulet Alice , Mignot Cyril , Missirian Chantal , Morice-Picard Fanny , Moutton Sébastien , Nadeau Gwenaël , Pebrel-Richard Céline , Odent Sylvie , Paquis-Flucklinger Véronique , Pasquier Laurent , Philip Nicole , Plutino Morgane , Pons Linda , Portnoï Marie-France , Prieur Fabienne , Puechberty Jacques , Putoux Audrey , Rio Marlène , Rooryck-Thambo Caroline , Rossi Massimiliano , Sarret Catherine , Satre Véronique , Siffroi Jean-Pierre , Till Marianne , Touraine Renaud , Toutain Annick , Toutain Jérome , Valence Stéphanie , Verloes Alain , Whalen Sandra , Edery Patrick , Tabet Anne-Claude , Sanlaville Damien 
Published: March 2019

BackgroundBalanced 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.MethodsBreakpoints 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.ResultsAmong 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.ConclusionPaired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.