title: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. radhakrishna.uppala@unige.ch
authors.forename: Uppala
authors.initials: U
authors.lastname: Radhakrishna
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Nath
authors.forename: Ken
authors.initials: K
authors.lastname: McElreavey
authors.forename: Uppala
authors.initials: U
authors.lastname: Ratnamala
authors.forename: Celi
authors.initials: C
authors.lastname: Sun
authors.forename: Amit K
authors.initials: AK
authors.lastname: Maiti
authors.forename: Maryline
authors.initials: M
authors.lastname: Gagnebin
authors.forename: Frédérique
authors.initials: F
authors.lastname: Béna
authors.forename: Heather L
authors.initials: HL
authors.lastname: Newkirk
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Merlin G
authors.initials: MG
authors.lastname: Butler
mesh_terms: D058674:Chromosome Duplication; D002878:Chromosomes, Human, Pair 1; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006554:Hernia, Umbilical / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide