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Évaluation Du Caryotype Moléculaire En Tant Qu'outil Diagnostique Chez

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Évaluation Du Caryotype Moléculaire En Tant Qu'outil Diagnostique Chez Université de Montréal Évaluation du caryotype moléculaire en tant qu’outil diagnostique chez les enfants avec déficience intellectuelle et/ou malformations congénitales par Guylaine D’Amours Programme de Sciences biomédicales Faculté de Médecine Mémoire présenté à la Faculté des études supérieures et postdoctorales en vue de l’obtention du grade de Maître ès science en Sciences biomédicales Mai 2013 © Guylaine D’Amours, 2013 Université de Montréal Faculté des études supérieures et postdoctorales Ce mémoire intitulé : Évaluation du caryotype moléculaire en tant qu’outil diagnostique chez les enfants avec déficience intellectuelle et/ou malformations congénitales Présenté par : Guylaine D’Amours a été évalué par un jury composé des personnes suivantes : Dre Josée Hébert, président-rapporteur Dre Emmanuelle Lemyre, directrice de recherche Dr Jacques L. Michaud, co-directeur Dre Alessandra M. Duncan, membre du jury iii RÉSUMÉ Le caryotype moléculaire permet d’identifier un CNV chez 10-14% des individus atteints de déficience intellectuelle et/ou de malformations congénitales. C’est pourquoi il s’agit maintenant de l’analyse de première intention chez ces patients. Toutefois, le rendement diagnostique n’est pas aussi bien défini en contexte prénatal et l’identification de CNVs de signification clinique incertaine y est particulièrement problématique à cause du risque d’interruption de grossesse. Nous avons donc testé 49 fœtus avec malformations majeures et un caryotype conventionnel normal avec une micropuce CGH pangénomique, et obtenu un diagnostic dans 8,2% des cas. Par ailleurs, des micropuces à très haute résolution combinant le caryotype moléculaire et le génotypage de SNPs ont récemment été introduites sur le marché. En plus d’identifier les CNVs, ces plateformes détectent les LOHs, qui peuvent indiquer la présence d’une mutation homozygote ou de disomie uniparentale. Ces anomalies pouvant être associées à la déficience intellectuelle ou à des malformations, leur détection est particulièrement intéressante pour les patients dont le phénotype reste inexpliqué. Cependant, le rendement diagnostique de ces plateformes n’est pas confirmé, et l’utilité clinique réelle des LOHs n’est toujours pas établie. Nous avons donc testé 21 enfants atteints de déficience intellectuelle pour qui les méthodes standards d’analyse génétique n’avaient pas résulté en un diagnostic, et avons pu faire passer le rendement diagnostique de 14,3% à 28,6% grâce à l’information fournie par les LOHs. Cette étude démontre l’utilité clinique d’une micropuce CGH pangénomique chez des fœtus avec malformations, de même que celle d’une micropuce SNP chez des enfants avec déficience intellectuelle. Mots-clés : Consanguinité, Déficience intellectuelle, Diagnostic prénatal, Disomie uniparentale, Hybridation génomique comparative (CGH), Malformations congénitales, Micropuce, Pertes d’hétérozygotie (LOH), Polymorphisme de nucléotide simple (SNP), Variation de nombre de copies de segment d’ADN (CNV). iv ABSTRACT Molecular karyotyping identifies a CNV in 10-14% of individuals affected with intellectual disability and/or congenital abnormalities. Therefore, it is now the first-tier analysis for these patients. However, the diagnostic yield is not as clear in the prenatal context, and the risk of pregnancy termination makes the detection of variants of uncertain clinical significance particularly problematic. We tested 49 fetuses with major malformations and a normal karyotype, using a pangenomic CGH array, and obtained a diagnosis in 8.2% of cases. Furthermore, high-resolution microarrays combining molecular karyotyping and SNP genotyping were recently introduced on the market. In addition to identifying CNVs, these platforms detect LOHs, which can indicate the presence of a homozygous mutation or of uniparental disomy. Since these abnormalities can be associated with intellectual disability or congenital abnormalities, their detection is of particular interest for patients whose phenotype remains unexplained. However, the diagnostic yield obtained with these platforms is not confirmed, and the real clinical value of LOH detection is not yet established. We tested 21 children affected with intellectual disability for whom standard genetic analyses failed to provide a diagnosis, and were able to increase the diagnostic yield from 14.3% to 28.6% as a result of the information provided by LOHs. This study shows the clinical usefulness of pangenomic CGH arrays in fetuses with malformation(s), as well as that of SNP arrays in children with intellectual disability. Keywords : Comparative genomic hybridization (CGH), Congenital abnormalities, Consanguinity, DNA copy number variation (CNV), Intellectual disability, Loss of heterozygosity (LOH), Microarray analysis, Prenatal diagnosis, Single nucleotide polymorphism (SNP), Uniparental disomy. v TABLE DES MATIÈRES RÉSUMÉ&...............................................................................................................................................................&iii! ABSTRACT&............................................................................................................................................................&iv! LISTE&DES&SIGLES&ET&ABRÉVIATIONS&...............................................................................................................&viii! LISTE&DES&TABLEAUX&............................................................................................................................................&x! LISTE&DES&FIGURES&.............................................................................................................................................&xi! REMERCIEMENTS&.............................................................................................................................................&xiii! 1! INTRODUCTION&.............................................................................................................................................&1! 1.1! GÉNÉRALITÉS!...........................................................................................................................................................!1! 1.2! VARIANTS!DU!NOMBRE!DE!COPIES!.......................................................................................................................!3! 1.2.1! Définition ............................................................................................................................ 3! 1.2.2! Mécanismes de formation ................................................................................................... 3! 1.2.3! Mécanismes pathogéniques ................................................................................................ 7! 1.2.4! Signification clinique .......................................................................................................... 9! 1.2.4.1! Éléments compliquant l’interprétation des résultats ................................................................. 12! 1.2.4.2! Outils informatiques nécessaires .............................................................................................. 14! 1.3! PERTES!D’HÉTÉROZYGOTIE!.................................................................................................................................!17! 1.3.1! Définition .......................................................................................................................... 17! 1.3.2! Ce que révèle la présence de pertes d’hétérozygotie ........................................................ 17! 1.3.2.1! Endogamie & consanguinité ..................................................................................................... 18! 1.3.2.2! Disomie uniparentale ................................................................................................................ 20! 1.3.3! Mécanismes pathogéniques associés aux pertes d’hétérozygotie ..................................... 24! 1.3.3.1! Transmission de mutations homozygotes ................................................................................. 24! 1.3.3.2! Gènes soumis à l’empreinte parentale ...................................................................................... 25! 1.4! MICROPUCES!EN!CYTOGÉNÉTIQUE!CLINIQUE!...................................................................................................!27! 1.4.1! Hybridation génomique comparative (CGH) ................................................................... 27! 1.4.1.1! Principe et évolution de la technique de CGH .......................................................................... 27! 1.4.1.2! Avantages et limites de la CGH ................................................................................................ 30! 1.4.2! Génotypage SNP sur micropuce ....................................................................................... 32! 1.4.2.1! Principe du génotypage SNP sur micropuce ............................................................................ 32! 1.4.2.2! Avantages et limites des micropuces SNP ................................................................................ 33! 1.4.3! Le caryotype moléculaire aujourd’hui .............................................................................. 37! 1.4.3.1! Combinaison CGH / génotypage SNP ...................................................................................... 37! 1.4.3.2! Utilisation actuelle des micropuces en clinique .......................................................................
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