Patients with PWS and related syndromes display differentially methylated regions involved in neurodevelopmental and nutritional trajectory

Clinical Epigenetics

Virginie Laurier¹  Catherine Molinas²  Emmanuelle Lacassagne³  Jean-Pierre Salles³  Sanaa Eddiry³  Maithé Tauber⁴  Éric Bieth⁵  Nicolas Franchitto⁶  Juliette Salles⁷ 

[1] Centre de Référence Prader-Willi, Hôpital Marin, APHP, Hendaye, France;Centre de Référence du Syndrome de Prader-Willi et Syndromes avec Troubles du Comportement Alimentaire, Unité D’endocrinologie, Obésités, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse, Toulouse, France;Infinity (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Paul Sabatier, Toulouse III, France;Infinity (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Paul Sabatier, Toulouse III, France;Centre de Référence du Syndrome de Prader-Willi et Syndromes avec Troubles du Comportement Alimentaire, Unité D’endocrinologie, Obésités, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse, Toulouse, France;Institut des Handicaps Neurologiques, Psychiatriques et Sensoriels, CHU de Toulouse, Toulouse, France;Service de Génétique Médicale, Hôpital Purpan, CHU, 31059, Toulouse, France;Service d’Addictologie Clinique, Urgences Réanimation Médecine, CHU de Toulouse, Toulouse, France;Université de Toulouse, Toulouse, France;Service de Psychiatrie et Psychologie, CHU de Toulouse, Toulouse, France;Infinity (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Paul Sabatier, Toulouse III, France;Institut des Handicaps Neurologiques, Psychiatriques et Sensoriels, CHU de Toulouse, Toulouse, France;

关键词: Neurodevelopmental disorder;    Genome-wide methylation analysis;    Prader–Willi;    SNORD116;    MAGEL2;   

DOI  :  10.1186/s13148-021-01143-0

来源: Springer

【 摘 要 】

BackgroundPrader–Willi syndrome is a rare genetic neurodevelopmental disorder caused by a paternal deficiency of maternally imprinted gene expression located in the chromosome 15q11–q13 region. Previous studies have demonstrated that several classes of neurodevelopmental disorders can be attributed to either over- or under-expression of specific genes that may lead to impairments in neuronal generation, differentiation, maturation and growth. Epigenetic changes that modify gene expression have been highlighted in these disorders. One recent study focused on epigenetic analysis and compared patients with PWS with patients with other imprinting disorders. No study, however, has yet focused on epigenetics in patients with PWS specifically by comparing the mutations associated with this syndrome.ObjectiveThis study investigated the epigenetic modifications in patients with PWS and patients with PWS-related disorders caused by inactivation of two genes of the PWS chromosomal region, SNORD116 and MAGEL2. Our approach also aimed to compare the epigenetic modifications in PWS and PWS-related disorders.MethodsWe compared genome-wide methylation analysis (GWAS) in seven blood samples from patients with PWS phenotype (five with deletions of the PWS locus, one with a microdeletion of SNORD116 and one with a frameshift mutation of MAGEL2 presenting with Schaaf–Yang syndrome), as well as two control patients. Controls were infants that had been studied for suspicion of genetic diseases that was not confirmed by the genetic analysis and the clinical follow-up.ResultsThe analysis identified 29,234 differentially methylated cytosines, corresponding to 5,308 differentially methylated regions (DMRs), which matched with 2,280 genes. The DMRs in patients with PWS were associated with neurodevelopmental pathways, endocrine dysfunction and social and addictive processes consistent with the key features of the PWS phenotype. In addition, the separate analysis for the SNORD116 and MAGEL2 deletions revealed that the DMRs associated with the SNORD116 microdeletion were found in genes implicated in metabolic pathways and nervous system development, whereas MAGEL2 mutations mostly concerned genes involved in macromolecule biosynthesis.ConclusionThe PWS is associated with epigenetic modifications with differences in SNORD116 and MAGEL2 mutations, which seem to be relevant to the different associated phenotypes.

【 授权许可】

CC BY