Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele

Abstract

Background Omphalocele is a congenital birth defect characterised by the presence of internal organs located outside of the ventral abdominal wall. The purpose of this study was to identify the underlying genetic mechanisms of a large autosomal dominant Caucasian family with omphalocele. Methods and findings A genetic linkage study was conducted in a large family with an autosomal dominant transmission of an omphalocele using a genome-wide single nucleotide polymorphism (SNP) array. The analysis revealed significant evidence of linkage (non-parametric NPL = 6.93, p=0.0001; parametric logarithm of odds (LOD) = 2.70 under a fully penetrant dominant model) at chromosome band 1p31.3. Haplotype analysis narrowed the locus to a 2.74 Mb region between markers rs2886770 (63014807 bp) and rs1343981 (65757349 bp). Molecular characterisation of this interval using array comparative genomic hybridisation followed by quantitative microsphere hybridisation analysis revealed a 710 kb duplication located at 63.5–64.2 Mb. All affected individuals who had an omphalocele and shared the haplotype were positive for this duplicated region, while the duplication was absent from all normal individuals of this family. Multipoint linkage analysis using the duplication as a marker yielded a maximum LOD score of 3.2 at 1p31.3 under a dominant model. The 710 kb duplication at 1p31.3 band contains seven known genes including FOXD3, ALG6, ITGB3BP, KIAA1799, DLEU2L, PGM1, and the proximal portion of ROR1. Importantly, this duplication is absent from the database of genomic variants. Conclusions The present study suggests that development of an omphalocele in this family is controlled by overexpression of one or more genes in the duplicated region. To the authors’ knowledge, this is the first reported association of an inherited omphalocele condition with a chromosomal rearrangement.

Genome-wide association study reveals a QTL and strong candidate genes for umbilical hernia in pigs on SSC14

“…Recently, Long et al [ 12 ] published a study suggesting a copy number variation (CNV) on SSC14 to be involved in development of umbilical hernia in pig. Also in humans some studies have been done on structural variations like deletions and duplications, suggesting that such variations also could play a role in occurrence of umbilical hernia [ 13 – 15 ]. Additionally, two studies in other species suggest that umbilical hernia is associated with the function of cyclin-dependent kinase inhibitory protein p57 KIP2 , a regulator of cell proliferation [ 16 , 17 ].…”

A review of genetic factors underlying craniorachischisis and omphalocele: Inspired by a unique trisomy 18 case

“…To date, only one genetic link in nonsyndromic and single defect cases has been studied. The particular genetic linkage analysis of a single family with a high incidence of nonsyndromic OMP showed a 710 kb duplication on chromosome 1p31.3 present on all OMP phenotypes (Radhakrishna et al, ). Other genes involve multiple malformations, with OMP as one of the genetic consequences.…”

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

“…Approximatively 14% of all cases of omphalocele can be classified as isolated [ 2 ]. Despite several studies investigating the genetic causes [ 22 – 25 ] or environmental risk factors [ 24 ] involved in this malformation, the etiology of isolated omphalocele has not been fully elucidated. Kanagawa et al [ 23 ] described an extensive family with vertical transmission of isolated omphalocele, with nine subjects over three generations affected, suggesting an autosomal dominant pattern of inheritance.…”

“…Despite these observations, inherited alterations have never been identified in these families. More recently, a genomic duplication was found in a large pedigree with autosomal dominant transmission of isolated omphalocele [ 22 ]. Genetic analysis revealed that all affected individuals were positive for a duplication at chromosome 1p31.3, suggesting the involvement of one or more genes in the duplicated region, including FOXD3 , ALG6 , ITGB3BP , KIAA1799 , DLEU2L , PGM1 , and the proximal portion of ROR1 [ 22 ].…”