title: Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array-based analysis in Silver-Russell syndrome.
abstract: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous congenital disorder characterized by severe growth retardation. Hypomethylation of the differentially methylated region (DMR) of the H19 gene and uniparental disomy of maternal chromosome 7 is present in ∼45% of the patients with SRS so more than half of these patients have no known genetic etiology. We combined several molecular technologies including multiplex methylation polymerase chain reaction, methylation-sensitive multiple ligation probe-dependent amplification, and methylation-sensitive high-resolution melting to assess the epigenetic status of 34 patients with SRS. Additionally, we applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Thirteen patients (38.2%) had hypomethylation of the DMR of the H19 gene and none had uniparental disomy of maternal chromosome 7. The whole genome arrays identified five patients (14.7%) with microdeletions on chromosomes 1q23q24.3, 7p15.3, 13q31.3, 14q32.31, and 15q26.2qter, respectively. The overall mutation detection rate was 52.9% by the epigenetic study and the whole genome strategy. Although epimutation may be the major cause of SRS and can be identified by multiplex methylation polymerase chain reaction, the whole genome approach also provides information on the etiology of SRS. If no epimutation is identified in the patients with typical SRS, microdeletions should be suspected.
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, and Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shin-Yu
authors.initials: SY
authors.lastname: Lin
authors.forename: Chien-Nan
authors.initials: CN
authors.lastname: Lee
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Hung
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Tsai
authors.forename: Shuan-Pei
authors.initials: SP
authors.lastname: Lin
authors.forename: Ni-Chung
authors.initials: NC
authors.lastname: Li
authors.forename: Wu-Shiun
authors.initials: WS
authors.lastname: Hsieh
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Tung
authors.forename: Dau-Ming
authors.initials: DM
authors.lastname: Niu
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.forename: Lang-Yao
authors.initials: LY
authors.lastname: Chen
authors.forename: Mei-Ya
authors.initials: MY
authors.lastname: Fang
authors.forename: Mei-Pin
authors.initials: MP
authors.lastname: Tu
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Kuo
authors.forename: Chiou-Ya
authors.initials: CY
authors.lastname: Lin
authors.forename: Yi-Ning
authors.initials: YN
authors.lastname: Su
authors.forename: Hong-Nerng
authors.initials: HN
authors.lastname: Ho
mesh_terms: D002881:Chromosomes, Human, Pair 12; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D019175:DNA Methylation; D005784:Gene Amplification; D020869:Gene Expression Profiling; D014644:Genetic Variation; D018392:Genomic Imprinting; D006801:Humans; D019656:Loss of Heterozygosity; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D017384:Sequence Deletion; D056730:Silver-Russell Syndrome / Q000235:genetics*
chemical_list: C094335:H19 long non-coding RNA; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C103637:mesoderm specific transcript protein; D004247:DNA