title: Chromosome 21 scan in Down syndrome reveals DSCAM as a predisposing locus in Hirschsprung disease.
abstract: 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.
authors.affiliation: INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jannot
authors.forename: Anna
authors.initials: A
authors.lastname: Pelet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Henrion-Caude
authors.forename: Asma
authors.initials: A
authors.lastname: Chaoui
authors.forename: Marine
authors.initials: M
authors.lastname: Masse-Morel
authors.forename: Stacey
authors.initials: S
authors.lastname: Arnold
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Nadège
authors.initials: N
authors.lastname: Bondurand
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Françoise
authors.initials: F
authors.lastname: Clerget-Darpoux
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
mesh_terms: D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21; D017630:Connexins / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics*; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D000097002:Gap Junction beta-1 Protein
chemical_list: D015815:Cell Adhesion Molecules; D017630:Connexins; D000097002:Gap Junction beta-1 Protein; C110833:DSCAM protein, human