Chromosome 21 scan in Down syndrome reveals DSCAM as a predisposing locus in Hirschsprung disease

Hirschsprung disease (HSCR) genetics is a paradigm for the study and understanding of multigenic disorders. Association between Down syndrome and HSCR suggests that genetic factors that predispose to HSCR map to chromosome 21. To identify these additional factors, we performed a dose-dependent assoc...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2013-05, Vol.8 (5), p.e62519-e62519
Main Authors: Jannot, Anne-Sophie, Pelet, Anna, Henrion-Caude, Alexandra, Chaoui, Asma, Masse-Morel, Marine, Arnold, Stacey, Sanlaville, Damien, Ceccherini, Isabella, Borrego, Salud, Hofstra, Robert M W, Munnich, Arnold, Bondurand, Nadège, Chakravarti, Aravinda, Clerget-Darpoux, Françoise, Amiel, Jeanne, Lyonnet, Stanislas
Format: Article
Language:English
Subjects:
Adaptation
Analysis
Binding Sites
Biology
Cell Adhesion Molecules - genetics
Chromosome 21
Chromosomes
Chromosomes, Human, Pair 21
Congenital diseases
Connexins - genetics
Consortia
Down syndrome
Down Syndrome - genetics
Down's syndrome
DSCAM protein
Enteric nervous system
Gap Junction beta-1 Protein
Gene expression
Gene Regulatory Networks
Genes
Genetic aspects
Genetic Association Studies
Genetic factors
Genetic Loci
Genetic Predisposition to Disease
Genetics
Genomics
Hirschsprung Disease - genetics
Hirschsprung's disease
Humans
Kinases
Linkage disequilibrium
Loci
Medical research
Medicine
Methods
Mutation
Nervous system
Network analysis
Neural cell adhesion molecule
Parents
Patients
Polymorphism, Single Nucleotide
Protein Binding
Single-nucleotide polymorphism
Sox10 protein
Susceptibility
White people
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Hirschsprung disease (HSCR) genetics is a paradigm for the study and understanding of multigenic disorders. Association between Down syndrome and HSCR suggests that genetic factors that predispose to HSCR map to chromosome 21. To identify these additional factors, we performed a dose-dependent association study on chromosome 21 in Down syndrome patients with HSCR. Assessing 10,895 SNPs in 26 Caucasian cases and their parents led to identify two associated SNPs (rs2837770 and rs8134673) at chromosome-wide level. Those SNPs, which were located in intron 3 of the DSCAM gene within a 19 kb-linkage disequilibrium block region were in complete association and are consistent with DSCAM expression during enteric nervous system development. We replicated the association of HSCR with this region in an independent sample of 220 non-syndromic HSCR Caucasian patients and their parents. At last, we provide the functional rationale to the involvement of DSCAM by network analysis and assessment of SOX10 regulation. Our results reveal the involvement of DSCAM as a HSCR susceptibility locus, both in Down syndrome and HSCR isolated cases. This study further ascertains the chromosome-scan dose-dependent methodology used herein as a mean to map the genetic bases of other sub-phenotypes both in Down syndrome and other aneuploidies.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0062519