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.

Sequence variants identification at the KCNQ1OT1: TSS differentially Methylated region in isolated omphalocele cases / B. Maria Francesca, M. Calvello, L. Paganini, L. Pezzani, M. Baccarin, L. Fontana, S.M. Sirchia, G. Silvana, L. Canazza, L. Ernesto, L.L. Colombo, L. Faustina, F. Mosca, S.M. Tabano, M.R. Miozzo. - In: BMC MEDICAL GENETICS. - ISSN 1471-2350. - 18:1(2017 Oct 18), pp. 115.1-115.9.

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

M. Calvello;L. Paganini;L. Pezzani;M. Baccarin;L. Fontana;S.M. Sirchia;L. Canazza;L.L. Colombo;F. Mosca;S.M. Tabano;M.R. Miozzo
2017-10-18

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.
Abdominal wall defects; Beckwith-Wiedemann syndrome; CDKN1C; Genomic imprinting; KCNQ1OT1:TSS-DMR; Omphalocele; Base Sequence; Beckwith-Wiedemann Syndrome; Child, Preschool; Chromosomes, Human, Pair 11; Consanguinity; Cyclin-Dependent Kinase Inhibitor p57; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Genomic Imprinting; Hernia, Umbilical; Humans; Infant; Infant, Newborn; Male; Mutation; Pedigree; Polymorphism, Single Nucleotide; Potassium Channels, Voltage-Gated; Sequence Deletion; Sequence Homology, Nucleic Acid; DNA Methylation; Genetic Variation; Transcription Initiation Site; Genetics; Genetics (clinical)
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/542749
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