Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

L. Fontana, M.F. Bedeschi, S. Maitz, A. Cereda, C. Faré, S. Motta, A. Seresini, P. D’Ursi, A. Orro, V. Pecile, M. Calvello, A. Selicorni, F. Lalatta, D. Milani, S.M. Sirchia, M. Miozzo, S. Tabano

Research output: Contribution to journalArticle


The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID. © 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Original languageEnglish
Pages (from-to)897-909
Number of pages13
Issue number9
Publication statusPublished - 2018


  • Beckwith-Wiedemann syndrome
  • epigenotype-phenotype correlations
  • multilocus imprinting disturbances
  • Silver-Russell syndrome
  • targeted next-generation sequencing
  • amino acid
  • nucleotide binding protein
  • abdominal wall defect
  • Article
  • Beckwith Wiedemann syndrome
  • chromosome 11p
  • clinical article
  • cohort analysis
  • computer model
  • controlled study
  • DNA binding
  • DNA methylation
  • epigenetics
  • female
  • gene
  • gene locus
  • gene mutation
  • genetic disorder
  • genome imprinting
  • genotype
  • human
  • macroglossia
  • male
  • maternal hypomethylation syndrome
  • methylation
  • missense mutation
  • multilocus imprinting disturbance
  • nevus flammeus
  • next generation sequencing
  • NLRP2 gene
  • phenotype
  • protein conformation
  • protein function
  • pyrosequencing
  • Silver Russell syndrome
  • ZFP42 gene

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