Sequence variants identification at the KCNQ1OT1:TSS differentially Methylated region in isolated omphalocele cases

BMC Med Genet. 2017 Oct 18;18(1):115. doi: 10.1186/s12881-017-0470-z.

Abstract

Background: Omphalocele is a congenital midline ventral body wall defect that can exist as isolated malformation or as part of a syndrome. It can be considered one of the major and most frequent clinical manifestation of Beckwith-Wiedemann Syndrome (BWS) in case of loss of methylation at KCNQ1OT1: Transcription Star Site-Differentially Methylated Region (TSS-DMR) or in presence of CDKN1C mutations. The isolated form of the omphalocele accounts approximately for about the 14% of the total cases and its molecular etiology has never been fully elucidated.

Methods: Given the tight relationship with BWS, we hypothesized that the isolated form of the omphalocele could belong to the heterogeneous spectrum of the BWS associated features, representing an endophenotype with a clear genetic connection. We therefore investigated genetic and epigenetic changes affecting BWS imprinted locus at 11p15.5 imprinted region, focusing in particular on the KCNQ1OT1:TSS DMR.

Results: We studied 21 cases of isolated omphalocele detected during pregnancy or at birth and identified the following rare maternally inherited variants: i) the non-coding variant G > A at nucleotide 687 (NR_002728.3) at KCNQ1OT1:TSS-DMR, which alters the methylation pattern of the imprinted allele, in one patient; ii) the deletion c.624-629delGGCCCC at exon 1 of CDKN1C, with unknown clinical significance, in two unrelated cases.

Conclusions: Taken together, these findings suggest that KCNQ1OT1:TSS-DMR could be a susceptibility locus for the isolated omphalocele.

Keywords: Abdominal wall defects; Beckwith-Wiedemann syndrome; CDKN1C; Genomic imprinting; KCNQ1OT1:TSS-DMR; Omphalocele.

MeSH terms

  • Base Sequence
  • Beckwith-Wiedemann Syndrome / genetics
  • Beckwith-Wiedemann Syndrome / pathology
  • Child, Preschool
  • Chromosomes, Human, Pair 11 / genetics
  • Consanguinity
  • Cyclin-Dependent Kinase Inhibitor p57 / genetics
  • DNA Methylation*
  • DNA Mutational Analysis / methods
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation*
  • Genomic Imprinting
  • Hernia, Umbilical / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mutation
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Potassium Channels, Voltage-Gated / genetics
  • Sequence Deletion
  • Sequence Homology, Nucleic Acid
  • Transcription Initiation Site*

Substances

  • CDKN1C protein, human
  • Cyclin-Dependent Kinase Inhibitor p57
  • KCNQ1OT1 long non-coding RNA, human
  • Potassium Channels, Voltage-Gated