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.
Highlights
Hirschsprung disease (HSCR, aganglionic megacolon) is the most frequent genetic cause of congenital intestinal obstruction
DSCAM has been regarded as an appealing candidate gene accounting for the increased prevalence of HSCR in patients with Down syndrome (DS)
DSCAM was shown to map to HSCR critical region [7] in patients with DS as well as to the genomic region associated with HSCR in a large Mennonite kindred [21]
Summary
Hirschsprung disease (HSCR, aganglionic megacolon) is the most frequent genetic cause of congenital intestinal obstruction. Genetic factor(s) on chromosome 21 are suspected to increase HSCR susceptibility. Two approaches have been used to identify genetic factors on chromosome 21 in these patients. The first one was to determine the shorter region of overlap (SRO) between segmental trisomy 21 and HSCR. This led to identify a region spanning 33.5–46.25 Mb on chromosome 21 [7]. The second approach consisted to analyze gene expression studies in the enteric nervous system of HSCR mouse models. This led to identify 9 genes mapping to the syntenic mouse DS critical region [8]. No gene on chromosome 21 was demonstrated to increase their susceptibility to HSCR
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