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

Uppala Radhakrishna; Swapan K Nath; Ken McElreavey; Uppala Ratnamala; Celi Sun; Amit K Maiti; Maryline Gagnebin; Frédérique Béna; Heather L Newkirk; Andrew J Sharp; David B Everman; Jeffrey C Murray; Charles E Schwartz; Stylianos E Antonarakis; Merlin G Butler

doi:10.1136/jmedgenet-2012-100826

Back

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

Journal article

Open access

Peer reviewed

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

Uppala Radhakrishna, Swapan K Nath, Ken McElreavey, Uppala Ratnamala, Celi Sun, Amit K Maiti, Maryline Gagnebin, Frédérique Béna, Heather L Newkirk, Andrew J Sharp, …

Journal of medical genetics, Vol.49(4), pp.270-276

04/2012

DOI: 10.1136/jmedgenet-2012-100826

PMCID: PMC5312754

PMID: 22499347

Files and links (1)

url

http://doi.org/10.1136/jmedgenet-2012-100826View

Open Access

Abstract

BackgroundOmphalocele 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 findingsA 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.ConclusionsThe 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.

Details

Title: Subtitle: Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele
Creators: Uppala Radhakrishna - Green Cross Voluntary Blood Bank, Paldi, Ahmedabad, India
Swapan K Nath - Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
Ken McElreavey - Reproduction, Fertility and Populations, Department of Developmental Biology, Institut Pasteur, Paris, France
Uppala Ratnamala - Department of Pharmacology, Creighton University, Omaha, Nebraska, USA
Celi Sun - Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
Amit K Maiti - Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
Maryline Gagnebin - Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
Frédérique Béna - Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
Heather L Newkirk - Clinical Reference Laboratory, Inc.— Quivira Road, Lenexa, Kansas, USA
Andrew J Sharp - Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
David B Everman - Center for Molecular Studies, Greenwood Genetic Center, Greenwood, South Carolina, USA
Jeffrey C Murray - Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
Charles E Schwartz - Center for Molecular Studies, Greenwood Genetic Center, Greenwood, South Carolina, USA
Stylianos E Antonarakis - Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
Merlin G Butler - Department of Pediatrics, Kansas University Medical Center, Kansas City, Kansas, USA
Resource Type: Journal article
Publication Details: Journal of medical genetics, Vol.49(4), pp.270-276
DOI: 10.1136/jmedgenet-2012-100826
PMID: 22499347
PMCID: PMC5312754
NLM abbreviation: J Med Genet
ISSN: 0022-2593
eISSN: 1468-6244
Language: English
Date published: 04/2012
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025410002771

Metrics

24 Record Views

9 Times Cited - Web of Science