title: Array-based DNA methylation analysis in individuals with developmental delay/intellectual disability and normal molecular karyotype.
abstract: Despite recent progress in molecular karyotyping and clinical sequencing the cause of intellectual disability in a considerable subset of individuals affected by this phenotype remains elusive. As intellectual disability is also a feature of various imprinting disorders and some monogenic forms of intellectual disability are caused by epigenetic modifiers we hypothesized that changes in DNA methylation might be associated with or even causative in some cases of intellectual disability. Therefore, we performed a DNA methylation analysis of peripheral blood samples from 82 patients with intellectual disability and additional features using the HumanMethylation450 BeadChip. The findings were compared to that of 19 normal controls. Differentially methylated loci were validated by bisulfite pyrosequencing. On a global level, we failed to detect a robust DNA methylation signature segregating individuals with intellectual disability from controls. Using an individual approach, we identified 157 regions showing individual DNA methylation changes in at least one patient. These correlated to 107 genes including genes linked to conditions associated with intellectual disability, namely COLEC11, SHANK2, GLI2 and KCNQ2, as well as imprinted genes like FAM50B and MEG3. The latter was suggestive of an undiagnosed Temple syndrome which could be confirmed by diagnostic tests. Subsequent in-depth analysis of imprinted loci revealed DNA methylation changes at additional imprinted loci, i.e. PPIEL, IGF2R, MEG8 and MCTS2/HM13, in up to five patients. Our findings indicate that imprinting disorders are rare but probably under-diagnosed in patients with intellectual disability and moreover point to DNA methylation changes as potential alternative means to identify deregulated genes involved in the pathogenesis of intellectual disability.
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kolarova
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Tangen
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bens
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Gutwein
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Kautza
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32 St, 60-479 Poznań, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rydzanicz
authors.affiliation: Department of Neuropediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stephani
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: caliebe@medgen.uni-kiel.de.
authors.forename: Almuth
authors.initials: A
authors.lastname: Caliebe
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D056426:Genetic Loci; D018392:Genomic Imprinting; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D059785:Karyotype; D008297:Male; D046228:Microarray Analysis; D010641:Phenotype
keywords: DNA methylation; Genomic imprinting; Intellectual disability; Temple syndrome