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Hum Mutat. 2017 Jan;38(1):105-111. doi: 10.1002/humu.23131. Epub 2016 Oct 26.

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

Author information

1
INSERM, UMR_S 938, CDR Saint-Antoine, Paris, F-75012, France.
2
Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, F-75012, France.
3
AP-HP, Hôpital Trousseau, Service d'explorations fonctionnelles endocriniennes, Paris, 75571, France.
4
Epigenetics Programme, The Babraham Institute, Cambridge, UK.
5
MAGIC Foundation, RSS/SGA Research and Education Fund, Oak Park, Illinois.
6
Centre Hospitalier Intercommunal, Service de Pédiatrie, Poissy, France.
7
INSERM U933, Service de Génétique et d'Embryologie Médicales, Paris, 75571, France.
8
AP-HP, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, Paris, 75571, France.
9
Département de Génétique, CRICM UPMC INSERM UMR_S975/CNRS UMR 7225, GH Pitié-Salpêtrière, APHP, Paris, France.
10
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA.

Abstract

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.

KEYWORDS:

IGF2/H19 imprinted domain; Silver-Russell syndrome; deletions; hypomethylation; imprinting control region 1

PMID:
27701793
DOI:
10.1002/humu.23131
[Indexed for MEDLINE]

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