Susanne Bens1, Julia Kolarova1, Jasmin Beygo2, Karin Buiting2, Almuth Caliebe1, Thomas Eggermann3, Gabriele Gillessen-Kaesbach4, Dirk Prawitt5, Susanne Thiele-Schmitz6, Matthias Begemann3, Thorsten Enklaar5, Jana Gutwein1, Andrea Haake1, Ulrike Paul1, Julia Richter1, Lukas Soellner3, Inga Vater1, David Monk7, Bernhard Horsthemke2, Ole Ammerpohl1, Reiner Siebert1. 1. Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany. 2. Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, D 45122 Essen, Germany. 3. Institute of Human Genetics, University Hospital Aachen, D 52074 Aachen, Germany. 4. Institut für Humangenetik Lübeck, Universität zu Lübeck, D 23562 Lübeck, Germany. 5. Section of Molecular Pediatrics University Medical Centre of the Johannes Gutenberg-University Mainz, D 55131 Mainz, Germany. 6. Division of Experimental Paediatric Endocrinology & Diabetes, Department of Paediatrics, University of Lübeck, D 23562 Lübeck, Germany. 7. Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Cancer Epigenetic & Biology Program (PEBC), Catalan Institute of Oncology, Hospital Duran i Reynals Barcelona, Barcelona, ES 08907, Spain.
Abstract
AIM: To characterize the genotypic and phenotypic extent of multilocus imprinting disturbances (MLID). MATERIALS & METHODS: We analyzed 37 patients with imprinting disorders (explorative cohort) for DNA methylation changes using the Infinium HumanMethylation450 BeadChip. For validation, three independent cohorts with imprinting disorders or cardinal features thereof were analyzed (84 patients with imprinting disorders, 52 with growth disorder, 81 with developmental delay). RESULTS: In the explorative cohort 21 individuals showed array-based MLID with each one displaying an Angelman or Temple syndrome phenotype, respectively. Epimutations in ZDBF2 and FAM50B were associated with severe MLID regarding number of affected regions. By targeted analysis we identified methylation changes of ZDBF2 and FAM50B also in the three validation cohorts. CONCLUSION: We corroborate epimutations in ZDBF2 and FAM50B as frequent changes in MLID whereas these rarely occur in other patients with cardinal features of imprinting disorders. Moreover, we show cell lineage specific differences in the genomic extent of FAM50B epimutation.
AIM: To characterize the genotypic and phenotypic extent of multilocus imprinting disturbances (MLID). MATERIALS & METHODS: We analyzed 37 patients with imprinting disorders (explorative cohort) for DNA methylation changes using the Infinium HumanMethylation450 BeadChip. For validation, three independent cohorts with imprinting disorders or cardinal features thereof were analyzed (84 patients with imprinting disorders, 52 with growth disorder, 81 with developmental delay). RESULTS: In the explorative cohort 21 individuals showed array-based MLID with each one displaying an Angelman or Temple syndrome phenotype, respectively. Epimutations in ZDBF2 and FAM50B were associated with severe MLID regarding number of affected regions. By targeted analysis we identified methylation changes of ZDBF2 and FAM50B also in the three validation cohorts. CONCLUSION: We corroborate epimutations in ZDBF2 and FAM50B as frequent changes in MLID whereas these rarely occur in other patients with cardinal features of imprinting disorders. Moreover, we show cell lineage specific differences in the genomic extent of FAM50B epimutation.
Entities:
Keywords:
DNA methylation; FAM50B; MLID; ZDBF2; imprinting; multi-locus imprinting disturbances
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