Abstract
BackgroundOmphalocele 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.MethodsGiven 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.ResultsWe 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.ConclusionsTaken together, these findings suggest that KCNQ1OT1:TSS-DMR could be a susceptibility locus for the isolated omphalocele.
Highlights
Omphalocele is a congenital midline ventral body wall defect that can exist as isolated malformation or as part of a syndrome
We studied 21 cases with isolated omphalocele diagnosed during pregnancy or at birth and we investigated molecular changes associated with Beckwith-Wiedemann Syndrome (BWS) to determine whether isolated omphalocele could belong to the heterogeneous spectrum of BWS associated features
We considered as “normal” Imprinted Maternally Expressed Transcript (H19)/Insulin Like Growth Factor 2 (IGF2):IG-Differentially Methylated Region (DMR) and KCNQ1OT1: Transcription Start Site (TSS)-DMR methylation ranges previously reported by our group [28, 29]
Summary
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. Omphalocele is a congenital midline ventral body wall defect characterized by the extrusion of abdominal viscera through the base of the umbilical cord. This malformation is related to the failure of the midgut loop to return to the peritoneal cavity after its herniation into the umbilical cord [1].
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