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Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele
  1. Uppala Radhakrishna1,2,3,
  2. Swapan K Nath4,
  3. Ken McElreavey5,
  4. Uppala Ratnamala6,
  5. Celi Sun4,
  6. Amit K Maiti4,
  7. Maryline Gagnebin1,
  8. Frédérique Béna1,
  9. Heather L Newkirk7,
  10. Andrew J Sharp1,
  11. David B Everman8,
  12. Jeffrey C Murray9,
  13. Charles E Schwartz8,
  14. Stylianos E Antonarakis1,
  15. Merlin G Butler10,11
  1. 1Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
  2. 2Department of Surgery-Transplant, Nebraska Medical Center, Omaha, Nebraska, USA
  3. 3Green Cross Voluntary Blood Bank, Paldi, Ahmedabad, India
  4. 4Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  5. 5Reproduction, Fertility and Populations, Department of Developmental Biology, Institut Pasteur, Paris, France
  6. 6Department of Pharmacology, Creighton University, Omaha, Nebraska, USA
  7. 7Clinical Reference Laboratory, Inc.—8433 Quivira Road, Lenexa, Kansas, USA
  8. 8Center for Molecular Studies, Greenwood Genetic Center, Greenwood, South Carolina, USA
  9. 9Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
  10. 10Department of Psychiatry & Behavioral Sciences, Kansas University Medical Center, Kansas City, Kansas, USA
  11. 11Department of Pediatrics, Kansas University Medical Center, Kansas City, Kansas, USA
  1. Correspondence to Dr Uppala Radhakrishna, Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue micehl servet, Geneva 1211, Switzerland; radhakrishna.uppala{at}


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.

  • Omphalocele
  • autosomal dominant
  • 1p31.3 duplication
  • genome-wide linkage
  • academic medicine
  • cell biology
  • complex traits
  • copy-number
  • genome-wide
  • reproductive medicine
  • molecular genetics
  • clinical genetics
  • genetic epidemiology
  • linkage
  • genetics

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  • UR and SKN equally contributed.

  • Funding The study was supported in part by Green Cross Blood Bank, Ahmedabad, Gujarat, India. SKN is supported by Oklahoma Medical Research Foundation institutional grant 9124, for linkage analysis. KM is supported by a GIS-Institut des Maladies Rare grant. AJS is supported by funding from the European Community's Seventh Framework Program under grant agreement 219250.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics committee of University of Nebraska Medical Center, Nebraska, USA.

  • Provenance and peer review Not commissioned; externally peer reviewed.