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Paternal deletion of the 11p15.5 centromeric-imprinting control region is associated with alteration of imprinted gene expression and recurrent severe intrauterine growth restriction
  1. Agostina De Crescenzo1,
  2. Angela Sparago1,2,
  3. Flavia Cerrato1,
  4. Orazio Palumbo3,
  5. Massimo Carella3,
  6. Marco Miceli2,4,
  7. Moshe Bronshtein5,
  8. Andrea Riccio1,2,
  9. Yuval Yaron6
  1. 1Department of Environmental Science, Second University of Naples, Caserta, Italy
  2. 2Institute of Genetics and Biophysics A.Buzzati-Traverso, CNR, Naples, Italy
  3. 3Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
  4. 4Department of General Pathology, Second University of Naples, Napoli, Italy
  5. 5Rambam Medical Center and Faculty of Medicine, Technion, Haifa, Israel
  6. 6Prenatal Diagnosis Unit, Genetic Institute, Tel Aviv Sourasky Medical Center & Tel Aviv University, Tel Aviv, Israel
  1. Correspondence to Dr Andrea Riccio, Department of Environmental Science, Second University of Naples, Caserta 81100, Italy; Andrea.Riccio{at}unina2.it

Abstract

Background Heterogeneous molecular defects affecting the 11p15.5 imprinted gene cluster are associated with the opposite growth disorders Beckwith-Wiedemann Syndrome (BWS) and Silver Russell syndrome (SRS). Maternal deletions of the centromeric domain usually result in BWS, but paternal deletions have been so far associated with normal phenotype. Here we describe a case of recurrent severe Intra-Uterine Growth Restriction (IUGR) with paternal transmission of an 11p15.5 60 kb deletion.

Methods and results Chromosome microarray (CMA), PCR and DNA sequencing analyses showed that two fetuses conceived by a normal couple inherited from their father a 60 kb deletion encompassing the Imprinting Control Region of the 11p15.5 centromeric domain. The two fetuses died in utero with severe growth restriction. PCR amplification of parental DNAs indicated that the father carried the mutation in the mosaic state. DNA methylation and gene expression analyses showed that the deletion led to an imprinting alteration restricted to the centromeric domain and resulting in silencing of KCNQ1OT1 and activation of CDKN1C and PHLDA2.

Conclusions Our data demonstrate that the phenotype associated with 11p15.5 deletions is strongly influenced by the size of the region involved and indicate imprinting defects leading to CDKN1C and PHLDA2 activation as cause of severe IUGR.

  • Epigenetics
  • Imprinting
  • Chromosomal
  • Molecular genetics

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