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 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.

[1]  S. Borrego,et al.  Comprehensive Analysis of NRG1 Common and Rare Variants in Hirschsprung Patients , 2012, PloS one.

[2]  S. Moore,et al.  Intronic RET gene variants in Down syndrome-associated Hirschsprung disease in an African population. , 2012, Journal of pediatric surgery.

[3]  Michael K. Ng,et al.  SNP and gene networks construction and analysis from classification of copy number variations data , 2011, BMC Bioinformatics.

[4]  Seneca L. Bessling,et al.  Steroid hormone modulation of RET through two estrogen responsive enhancers in breast cancer. , 2011, Human molecular genetics.

[5]  P. Sham,et al.  Mutations in the NRG1 gene are associated with Hirschsprung disease , 2011, Human Genetics.

[6]  M. Wegner,et al.  L1cam acts as a modifier gene during enteric nervous system development , 2010, Neurobiology of Disease.

[7]  M. Gershon.  Developmental determinants of the independence and complexity of the enteric nervous system , 2010, Trends in Neurosciences.

[8]  Lora J. H. Bean,et al.  Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome , 2010, Genetic epidemiology.

[9]  M. Gerstein,et al.  The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies , 2009, Proceedings of the National Academy of Sciences.

[10]  A. Chakravarti,et al.  Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome–Hirschsprung disease association , 2009, Human mutation.

[11]  K. Yamakawa,et al.  DSCAM Deficiency Causes Loss of Pre-Inspiratory Neuron Synchroneity and Perinatal Death , 2009, The Journal of Neuroscience.

[12]  P. Sham,et al.  Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease , 2009, Proceedings of the National Academy of Sciences.

[13]  Y. Rao,et al.  DSCAM functions as a netrin receptor in commissural axon pathfinding , 2009, Proceedings of the National Academy of Sciences.

[14]  Yan Lin,et al.  Smarter clustering methods for SNP genotype calling , 2008, Bioinform..

[15]  Tao Han,et al.  Assessing batch effects of genotype calling algorithm BRLMM for the Affymetrix GeneChip Human Mapping 500 K array set using 270 HapMap samples , 2008, BMC Bioinformatics.

[16]  M. Tessier-Lavigne,et al.  DSCAM Is a Netrin Receptor that Collaborates with DCC in Mediating Turning Responses to Netrin-1 , 2008, Cell.

[17]  A. Munnich,et al.  Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease , 2007, Human mutation.

[18]  A Chakravarti,et al.  Hirschsprung disease, associated syndromes and genetics: a review , 2001, Journal of Medical Genetics.

[19]  V. Pachnis,et al.  Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Schachner,et al.  The cell adhesion molecule l1 is required for chain migration of neural crest cells in the developing mouse gut. , 2006, Gastroenterology.

[21]  BRLMM : an Improved Genotype Calling Method for the GeneChip ® Human Mapping 500 K Array Set , 2006 .

[22]  Clifford A. Meyer,et al.  Chromosome-Wide Mapping of Estrogen Receptor Binding Reveals Long-Range Regulation Requiring the Forkhead Protein FoxA1 , 2005, Cell.

[23]  M. Farrall,et al.  Integrating Case‐control and TDT Studies , 2005 .

[24]  M Farrall,et al.  Integrating case-control and TDT studies. , 2005, Annals of human genetics.

[25]  E. Grice,et al.  A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk , 2005, Nature.

[26]  A. Tremblay,et al.  Selective hormone-dependent repression of estrogen receptor beta by a p38-activated ErbB2/ErbB3 pathway , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[27]  M. Gershon,et al.  Developmental biology of the enteric nervous system: pathogenesis of Hirschsprung's disease and other congenital dysmotilities. , 2004, Seminars in pediatric surgery.

[28]  Eleanor Feingold,et al.  Linkage disequilibrium mapping in trisomic populations: Analytical approaches and an application to congenital heart defects in Down syndrome , 2004, Genetic epidemiology.

[29]  E. Monrós,et al.  Hydrocephalus and Hirschsprung's disease with a mutation of L1CAM , 2004, Journal of Human Genetics.

[30]  Eleanor Feingold,et al.  A trisomic transmission disequilibrium test , 2004, Genetic epidemiology.

[31]  M. Gershon,et al.  Netrins and DCC in the guidance of migrating neural crest-derived cells in the developing bowel and pancreas. , 2003, Developmental biology.

[32]  A. McCallion,et al.  Genomic variation in multigenic traits: Hirschsprung disease. , 2003, Cold Spring Harbor symposia on quantitative biology.

[33]  Misha Angrist,et al.  Segregation at three loci explains familial and population risk in Hirschsprung disease , 2002, Nature Genetics.

[34]  R. Hofstra,et al.  Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease? , 2002, American journal of medical genetics.

[35]  O. Dubourg,et al.  Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. , 2001, Human molecular genetics.

[36]  M. Campbell-Thompson,et al.  Immunolocalization of estrogen receptor alpha and beta in gastric epithelium and enteric neurons. , 2001, The Journal of endocrinology.

[37]  M. Wegner,et al.  The glial transcription factor Sox10 binds to DNA both as monomer and dimer with different functional consequences. , 2000, Nucleic acids research.

[38]  M. Wegner,et al.  Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. , 2000, Human molecular genetics.

[39]  M. Wegner,et al.  Protein Zero Gene Expression Is Regulated by the Glial Transcription Factor Sox10 , 2000, Molecular and Cellular Biology.

[40]  M. Ehm,et al.  Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. , 1998, American journal of human genetics.

[41]  D. Riethmacher,et al.  The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system. , 1998, Genes & development.

[42]  M. Wegner,et al.  Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[43]  K. Yamakawa,et al.  DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system. , 1998, Human molecular genetics.

[44]  W. Pavan,et al.  SOX10 mutation disrupts neural crest development in Dom Hirschsprung mouse model , 1998, Nature Genetics.

[45]  Y. Wada,et al.  Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM. , 1997, Journal of medical genetics.

[46]  T. Matise,et al.  Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. , 1994, Human molecular genetics.