Molecular and Clinical Studies in 138 Japanese Patients with Silver-Russell Syndrome

Tomoko Fuke, Seiji Mizuno, Toshiro Nagai, Tomonobu Hasegawa, Reiko Horikawa, Yoko Miyoshi, Koji Muroya, Tatsuro Kondoh, Chikahiko Numakura, Seiji Sato, Kazuhiko Nakabayashi, Chiharu Tayama, Kenichiro Hata, Shinichiro Sano, Keiko Matsubara, Masayo Kagami, Kazuki Yamazawa, Tsutomu Ogata

Research output: Contribution to journalArticle

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Abstract

Background: Recent studies have revealed relative frequency and characteristic phenotype of two major causative factors for Silver-Russell syndrome (SRS), i.e. epimutation of the H19-differentially methylated region (DMR) and uniparental maternal disomy 7 (upd(7)mat), as well as multilocus methylation abnormalities and positive correlation between methylation index and body and placental sizes in H19-DMR epimutation. Furthermore, rare genomic alterations have been found in a few of patients with idiopathic SRS. Here, we performed molecular and clinical findings in 138 Japanese SRS patients, and examined these matters. Methodology/Principal Findings: We identified H19-DMR epimutation in cases 1-43 (group 1), upd(7)mat in cases 44-52 (group 2), and neither H19-DMR epimutation nor upd(7)mat in cases 53-138 (group 3). Multilocus analysis revealed hyper- or hypomethylated DMRs in 2.4% of examined DMRs in group 1; in particular, an extremely hypomethylated ARHI-DMR was identified in case 13. Oligonucleotide array comparative genomic hybridization identified a ~3.86 Mb deletion at chromosome 17q24 in case 73. Epigenotype-phenotype analysis revealed that group 1 had more reduced birth length and weight, more preserved birth occipitofrontal circumference (OFC), more frequent body asymmetry and brachydactyly, and less frequent speech delay than group 2. The degree of placental hypoplasia was similar between the two groups. In group 1, the methylation index for the H19-DMR was positively correlated with birth length and weight, present height and weight, and placental weight, but with neither birth nor present OFC. Conclusions/Significance: The results are grossly consistent with the previously reported data, although the frequency of epimutations is lower in the Japanese SRS patients than in the Western European SRS patients. Furthermore, the results provide useful information regarding placental hypoplasia in SRS, clinical phenotypes of the hypomethylated ARHI-DMR, and underlying causative factors for idiopathic SRS.

Original languageEnglish
Article numbere60105
JournalPLoS One
Volume8
Issue number3
DOIs
Publication statusPublished - 2013 Mar 22

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Silver-Russell Syndrome
Silver
silver
clinical trials
Methylation
methylation
Phenotype
phenotype
Birth Weight
Brachydactyly
Parturition
comparative genomic hybridization
Language Development Disorders
Weights and Measures
Chromosome Deletion
Comparative Genomic Hybridization
Group delay
Body Size
Chromosomes
oligonucleotides

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Fuke, T., Mizuno, S., Nagai, T., Hasegawa, T., Horikawa, R., Miyoshi, Y., ... Ogata, T. (2013). Molecular and Clinical Studies in 138 Japanese Patients with Silver-Russell Syndrome. PLoS One, 8(3), [e60105]. https://doi.org/10.1371/journal.pone.0060105

Molecular and Clinical Studies in 138 Japanese Patients with Silver-Russell Syndrome. / Fuke, Tomoko; Mizuno, Seiji; Nagai, Toshiro; Hasegawa, Tomonobu; Horikawa, Reiko; Miyoshi, Yoko; Muroya, Koji; Kondoh, Tatsuro; Numakura, Chikahiko; Sato, Seiji; Nakabayashi, Kazuhiko; Tayama, Chiharu; Hata, Kenichiro; Sano, Shinichiro; Matsubara, Keiko; Kagami, Masayo; Yamazawa, Kazuki; Ogata, Tsutomu.

In: PLoS One, Vol. 8, No. 3, e60105, 22.03.2013.

Research output: Contribution to journalArticle

Fuke, T, Mizuno, S, Nagai, T, Hasegawa, T, Horikawa, R, Miyoshi, Y, Muroya, K, Kondoh, T, Numakura, C, Sato, S, Nakabayashi, K, Tayama, C, Hata, K, Sano, S, Matsubara, K, Kagami, M, Yamazawa, K & Ogata, T 2013, 'Molecular and Clinical Studies in 138 Japanese Patients with Silver-Russell Syndrome', PLoS One, vol. 8, no. 3, e60105. https://doi.org/10.1371/journal.pone.0060105
Fuke, Tomoko ; Mizuno, Seiji ; Nagai, Toshiro ; Hasegawa, Tomonobu ; Horikawa, Reiko ; Miyoshi, Yoko ; Muroya, Koji ; Kondoh, Tatsuro ; Numakura, Chikahiko ; Sato, Seiji ; Nakabayashi, Kazuhiko ; Tayama, Chiharu ; Hata, Kenichiro ; Sano, Shinichiro ; Matsubara, Keiko ; Kagami, Masayo ; Yamazawa, Kazuki ; Ogata, Tsutomu. / Molecular and Clinical Studies in 138 Japanese Patients with Silver-Russell Syndrome. In: PLoS One. 2013 ; Vol. 8, No. 3.
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AU - Fuke, Tomoko

AU - Mizuno, Seiji

AU - Nagai, Toshiro

AU - Hasegawa, Tomonobu

AU - Horikawa, Reiko

AU - Miyoshi, Yoko

AU - Muroya, Koji

AU - Kondoh, Tatsuro

AU - Numakura, Chikahiko

AU - Sato, Seiji

AU - Nakabayashi, Kazuhiko

AU - Tayama, Chiharu

AU - Hata, Kenichiro

AU - Sano, Shinichiro

AU - Matsubara, Keiko

AU - Kagami, Masayo

AU - Yamazawa, Kazuki

AU - Ogata, Tsutomu

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N2 - Background: Recent studies have revealed relative frequency and characteristic phenotype of two major causative factors for Silver-Russell syndrome (SRS), i.e. epimutation of the H19-differentially methylated region (DMR) and uniparental maternal disomy 7 (upd(7)mat), as well as multilocus methylation abnormalities and positive correlation between methylation index and body and placental sizes in H19-DMR epimutation. Furthermore, rare genomic alterations have been found in a few of patients with idiopathic SRS. Here, we performed molecular and clinical findings in 138 Japanese SRS patients, and examined these matters. Methodology/Principal Findings: We identified H19-DMR epimutation in cases 1-43 (group 1), upd(7)mat in cases 44-52 (group 2), and neither H19-DMR epimutation nor upd(7)mat in cases 53-138 (group 3). Multilocus analysis revealed hyper- or hypomethylated DMRs in 2.4% of examined DMRs in group 1; in particular, an extremely hypomethylated ARHI-DMR was identified in case 13. Oligonucleotide array comparative genomic hybridization identified a ~3.86 Mb deletion at chromosome 17q24 in case 73. Epigenotype-phenotype analysis revealed that group 1 had more reduced birth length and weight, more preserved birth occipitofrontal circumference (OFC), more frequent body asymmetry and brachydactyly, and less frequent speech delay than group 2. The degree of placental hypoplasia was similar between the two groups. In group 1, the methylation index for the H19-DMR was positively correlated with birth length and weight, present height and weight, and placental weight, but with neither birth nor present OFC. Conclusions/Significance: The results are grossly consistent with the previously reported data, although the frequency of epimutations is lower in the Japanese SRS patients than in the Western European SRS patients. Furthermore, the results provide useful information regarding placental hypoplasia in SRS, clinical phenotypes of the hypomethylated ARHI-DMR, and underlying causative factors for idiopathic SRS.

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