INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France.
PLoS One. 2013 May 6;8(5):e62519. doi: 10.1371/journal.pone.0062519. Print 2013.
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.
先天性巨结肠症（HSCR）遗传学是研究和理解多基因疾病的范例。唐氏综合征与 HSCR 之间的关联表明，易患 HSCR 的遗传因素映射到 21 号染色体上。为了确定这些其他因素，我们在患有 HSCR 的唐氏综合征患者的 21 号染色体上进行了剂量依赖性关联研究。评估了 26 名白种人病例及其父母的 10895 个 SNP，确定了两个相关的 SNP（rs2837770 和 rs8134673），达到染色体全基因组水平。这些 SNP 位于 DSCAM 基因的内含子 3 中，位于 19kb 连锁不平衡块区域内，完全关联，与肠神经系统发育过程中的 DSCAM 表达一致。我们在 220 名非综合征性 HSCR 白种人病例及其父母的独立样本中复制了该区域与 HSCR 的关联。最后，我们通过网络分析和 SOX10 调节评估提供了 DSCAM 参与的功能基础。我们的研究结果表明，DSCAM 作为 HSCR 的易感基因座，既参与唐氏综合征，也参与孤立性 HSCR。本研究进一步证实了本文中使用的染色体扫描剂量依赖性方法，作为在唐氏综合征和其他非整倍体中映射其他亚表型遗传基础的一种手段。
