Phenotypic spectrum and extent of DNA methylation defects associated with multilocus imprinting disturbances.
To characterize the genotypic and phenotypic extent of multilocus imprinting disturbances (MLID).



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).



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.



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.
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Susanne
S
Bens
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Julia
J
Kolarova
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, D 45122 Essen, Germany.
Jasmin
J
Beygo
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, D 45122 Essen, Germany.
Karin
K
Buiting
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Almuth
A
Caliebe
Institute of Human Genetics, University Hospital Aachen, D 52074 Aachen, Germany.
Thomas
T
Eggermann
Institut für Humangenetik Lübeck, Universität zu Lübeck, D 23562 Lübeck, Germany.
Gabriele
G
Gillessen-Kaesbach
Section of Molecular Pediatrics University Medical Centre of the Johannes Gutenberg-University Mainz, D 55131 Mainz, Germany.
Dirk
D
Prawitt
Division of Experimental Paediatric Endocrinology & Diabetes, Department of Paediatrics, University of Lübeck, D 23562 Lübeck, Germany.
Susanne
S
Thiele-Schmitz
Institute of Human Genetics, University Hospital Aachen, D 52074 Aachen, Germany.
Matthias
M
Begemann
Section of Molecular Pediatrics University Medical Centre of the Johannes Gutenberg-University Mainz, D 55131 Mainz, Germany.
Thorsten
T
Enklaar
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Jana
J
Gutwein
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Andrea
A
Haake
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Ulrike
U
Paul
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Julia
J
Richter
Institute of Human Genetics, University Hospital Aachen, D 52074 Aachen, Germany.
Lukas
L
Soellner
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Inga
I
Vater
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.
David
D
Monk
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, D 45122 Essen, Germany.
Bernhard
B
Horsthemke
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Ole
O
Ammerpohl
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, D 24105 Kiel, Germany.
Reiner
R
Siebert
D016022:Case-Control Studies; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA
D004268:DNA-Binding Proteins; C561457:FAM50B protein, human; D011506:Proteins; C000624166:ZDBF2 protein, human
DNA methylation; FAM50B; MLID; ZDBF2; imprinting; multi-locus imprinting disturbances