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

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

doi:10.1136/jmedgenet-2018-105778

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

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

Caroline Schluth-Bolard, Flavie Diguet, Nicolas Chatron, Pierre-Antoine Rollat-Farnier, Claire Bardel, Alexandra Afenjar, Florence Amblard, Jeanne Amiel, Sophie Blesson, Patrick Callier, …

Journal of Medical Genetics, Vol.56(8), pp.526-535

28/03/2019

DOI: https://doi.org/10.1136/jmedgenet-2018-105778

PMID: 30923172

Abstract

intellectual disability

chromosomal rearrangements

whole genome sequencing

structural variation

position effect

intellectual disability

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.

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Title: Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders
Creators - without role: Caroline Schluth-Bolard - Hôpital Femme Mère Enfant
Flavie Diguet - Université Claude Bernard Lyon 1
Nicolas Chatron - Hospices Civils de Lyon
Pierre-Antoine Rollat-Farnier
Claire Bardel - Laboratoire de Biométrie et Biologie Evolutive
Alexandra Afenjar - Sorbonne Université
Florence Amblard - Hôpital Couple Enfant
Jeanne Amiel - Hôpital Necker-Enfants Malades
Sophie Blesson - Centre Hospitalier Universitaire de Tours
Patrick Callier - Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
Yline Capri - Hôpital Robert-Debré
Patrick Collignon - Toulon Var Technologies
Marie-Pierre Cordier - Hôpital Femme Mère Enfant
Christine Coubes - Hôpital Arnaud de Villeneuve
Bénédicte Demeer - Centre Hospitalier Universitaire Amiens-Picardie
Annabelle Chaussenot - Centre Hospitalier Universitaire de Nice
Florence Demurger - Centre Hospitalier Universitaire de Rennes
Françoise Devillard - Centre Hospitalier Universitaire de Grenoble
Martine Doco-Fenzy - Université de Reims Champagne-Ardenne
Celine Dupont - Hôpital Robert-Debré
Jean-Michel Dupont - Hôpital Cochin
Sophie Dupuis-Girod - Hospices Civils de Lyon
Laurence Faivre - Inserm
Brigitte Gilbert-Dussardier - Université de Poitiers
Anne-Marie Guerrot - Charmo University
Marine Houlier - Hôpital Necker-Enfants Malades
Bertrand Isidor - Génétique Médicale & Génomique Fonctionelle
Sylvie Jaillard - Laboratoire de Génétique Cellulaire
Géraldine Joly-Helas - Université de Rouen Normandie
Valérie Kremer
Didier Lacombe - Hôpital Pellegrin
Cedric Le Caignec - Génétique Médicale & Génomique Fonctionelle
Aziza Lebbar - Hôpital Cochin
Marine Lebrun - Hôpital Nord
Gaetan Lesca - Hospices Civils de Lyon
James Lespinasse - Laboratoire de Génétique Cellulaire
Jonathan Levy - Hôpital Robert-Debré
Valérie Malan - Hôpital Necker-Enfants Malades
Michèle Mathieu-Dramard - Centre Hospitalier Universitaire Amiens-Picardie
Julie Masson - Centre de Recherche en Neurosciences de Lyon
Alice Masurel-Paulet - Université de Bourgogne
Cyril Mignot - Centre d'Épidémiologie sur les Causes Médicales de Décès
Chantal Missirian - Génétique Médicale & Génomique Fonctionelle
Fanny Morice-Picard - Université de Bordeaux
Sébastien Moutton - Hôpital Pellegrin
Gwenaël Nadeau - Laboratoire de Génétique Cellulaire
Céline Pebrel-Richard - Centre Hospitalier Universitaire de Clermont-Ferrand
Sylvie Odent - Institut de génétique et de développement de Rennes
Véronique Paquis-Flucklinger - Centre Hospitalier Universitaire de Nice
Laurent Pasquier - CIC Rennes
Nicole Philip - Génétique Médicale & Génomique Fonctionelle
Morgane Plutino - Centre Hospitalier Universitaire de Nice
Linda Pons - Université Claude Bernard Lyon 1
Marie-France Portnoi - Dept of Immunology, Genetics and Pathology
Fabienne Prieur - Hôpital Nord
Jacques Puechberty - Université de Montpellier, Institut de Génétique Humaine - IGH
Audrey Putoux - Hospices Civils de Lyon
Marlène Rio - Hôpital Necker-Enfants Malades
Caroline Rooryck-Thambo - Centre Hospitalier Universitaire de Bordeaux
Massimiliano Rossi - Centre de Recherche en Neurosciences de Lyon
Catherine Sarret - Centre Hospitalier Universitaire de Clermont-Ferrand
Veronique Satre - Centre Hospitalier Universitaire de Grenoble
Jean-Pierre Siffroi - Charmo University
Marianne Till - Hospices Civils de Lyon
Renaud Touraine - Hôpital Nord
Annick Toutain - Centre Hospitalier Universitaire de Tours
Jérôme Toutain - Hôpital Pellegrin
Stephanie Valence - Sorbonne Université
Alain Verloes - Hôpital Robert-Debré
Sandra Whalen - Sorbonne Université
Patrick Edery - Centre de Recherche en Neurosciences de Lyon
Anne-Claude Tabet - Département de génétique
Damien Sanlaville - Université Claude Bernard Lyon 1
Publication Details: Journal of Medical Genetics, Vol.56(8), pp.526-535
Grant note: French National Agency for Research
Identifiers: 9963386609311
Academic Unit: Institut de Génétique Humaine - IGH
Language: English
Resource Type: Journal article
Local Fields: hal-03863519