A novel IGF2/H19 domain triplication in the 11p15.5 imprinting region causing either Beckwith-Wiedemann or Silver-Russell syndrome in a single family.

Defects of 11p15.5 imprinting result in two growth disorders with opposite phenotypes: Beckwith-Wiedemann syndrome (BWS) characterized by overgrowth and Silver-Russell syndrome (SRS) associated with growth retardation. In a small group of patients with BWS and SRS, copy number variations (CNVs) involving the 11p15.5 region are observed; and their effects depend on the localization, size, and the parental mode of transmission. We report a novel IGF2/H19 domain cis-triplication in the 11p15.5 region identified in a girl with BWS and her father with symptoms of SRS. To the best of our knowledge, this is the first report of IGF2/H19 domain triplication associated with BWS or SRS and the second report of an additional copy of this region in an individual with clinical features of SRS. This study shows that paternal IGF2/H19 domain triplication results in BWS, gives additional support to the hypothesis that the maternal amplification of IGF2/H19 domain may lead to the manifestation of SRS and underlines difficulties of genetic counseling in patients with CNVs involving the 11p15.5 region. © 2016 Wiley Periodicals, Inc.

Jurkiewicz D ，Kugaudo M ，Skórka A ，Śmigiel R ，Smyk M ，Ciara E ，Chrzanowska K ，Krajewska-Walasek M ... -  《-》

New insights into the pathogenesis of Beckwith-Wiedemann and Silver-Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects.

The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS.

Demars J ，Rossignol S ，Netchine I ，Lee KS ，Shmela M ，Faivre L ，Weill J ，Odent S ，Azzi S ，Callier P ，Lucas J ，Dubourg C ，Andrieux J ，Le Bouc Y ，El-Osta A ，Gicquel C ... -  《-》

11p15 ICR1 Partial Deletions Associated with IGF2/H19 DMR Hypomethylation and Silver-Russell Syndrome.

The 11p15 region harbors the IGF2/H19 imprinted domain, implicated in fetal and postnatal growth. Silver-Russell syndrome (SRS) is characterized by fetal and postnatal growth failure, and is caused principally by hypomethylation of the 11p15 imprinting control region 1 (ICR1). However, the mechanisms leading to ICR1 hypomethylation remain unknown. Maternally inherited genetic defects affecting the ICR1 domain have been associated with ICR1 hypermethylation and Beckwith-Wiedemann syndrome (an overgrowth syndrome, the clinical and molecular mirror of SRS), and paternal deletions of IGF2 enhancers have been detected in four SRS patients. However, no paternal deletions of ICR1 have ever been associated with hypomethylation of the IGF2/H19 domain in SRS. We screened for new genetic defects within the ICR1 in a cohort of 234 SRS patients with hypomethylated IGF2/H19 domain. We report deletions close to the boundaries of ICR1 on the paternal allele in one familial and two sporadic cases of SRS with ICR1 hypomethylation. These deletions are associated with hypomethylation of the remaining CBS, and decreased IGF2 expression. These results suggest that these regions are most likely required to maintain methylation after fertilization. We estimate these anomalies to occur in about 1% of SRS cases with ICR1 hypomethylation.

Abi Habib W ，Brioude F ，Azzi S ，Salem J ，Das Neves C ，Personnier C ，Chantot-Bastaraud S ，Keren B ，Le Bouc Y ，Harbison MD ，Netchine I ... -  《-》

A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes.

Russo S ，Calzari L ，Mussa A ，Mainini E ，Cassina M ，Di Candia S ，Clementi M ，Guzzetti S ，Tabano S ，Miozzo M ，Sirchia S ，Finelli P ，Prontera P ，Maitz S ，Sorge G ，Calcagno A ，Maghnie M ，Divizia MT ，Melis D ，Manfredini E ，Ferrero GB ，Pecile V ，Larizza L ... -  《-》

A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient.

The IGF2/H19-imprinting control region (ICR1) functions as an insulator to methylation-sensitive binding of CTCF protein, and regulates imprinted expression of IGF2 and H19 in a parental origin-specific manner. ICR1 methylation defects cause abnormal expression of imprinted genes, leading to Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS). Not only ICR1 microdeletions involving the CTCF-binding site, but also point mutations and a small deletion of the OCT-binding site have been shown to trigger methylation defects in BWS. Here, mutational analysis of ICR1 in 11 BWS and 12 SRS patients with ICR1 methylation defects revealed a novel de novo point mutation of the OCT-binding site on the maternal allele in one BWS patient. In BWS, all reported mutations and the small deletion of the OCT-binding site, including our case, have occurred within repeat A2. These findings indicate that the OCT-binding site is important for maintaining an unmethylated status of maternal ICR1 in early embryogenesis.

Higashimoto K ，Jozaki K ，Kosho T ，Matsubara K ，Fuke T ，Yamada D ，Yatsuki H ，Maeda T ，Ohtsuka Y ，Nishioka K ，Joh K ，Koseki H ，Ogata T ，Soejima H ... -  《-》