Hirschsprung Disease, Susceptibility To, 6

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Retrieved

2019-09-22

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Omim

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Genes

EDN3, EDNRB, GDNF, RET, ZEB2, NRG1, SOX10, SEMA3D, SEMA3C, ECE1, GFRA1, NKX2-1, CAVIN2, MIR206, GAL, FZD3, NTRK3, RELN, AFAP1-AS1, WNT3A, MIR369, NRSN1, CELSR3, ARID1B, GAP43, MIR218-1, BMI1, MIR195, MIR128-1, MED12, LCT-AS1, UTP25, IHH, L1CAM, ERBB2, ITGB1, CD14, AEBP2, PHOX2B, PAX3, NRTN, KIFBP, PROKR1, DSCAM, PIGV, ASCL1, BDNF, TCF4, PIGO, RASGEF1A, COMT, RMRP, CSGALNACT2, MITF, KITLG, KIAA0586, RAD51, RPGRIP1L, RIMBP2, PIGN, RAD51C, SETBP1, SH2B1, EXOC6B, TBX1, B9D1, PGAP2, UBE2T, RREB1, SNAI2, KIAA0556, KIR2DS4, KIR2DL1, KIR2DS1, MBTPS2, NPHP1, SEC24C, SF3B4, MAD2L2, PIBF1, PIGL, POLR2F, NAA10, MKKS, XRCC2, GJB6, UFD1, ZNF423, HIRA, KRAS, KIT, KIR3DL1, CEP104, TMEM216, VRK2, TMEM138, CSPP1, AHI1, ARMC9, DDX59, BRIP1, DHCR7, SLX4, ABHD1, CREBBP, PIGY, TMEM67, PGAP3, CEP41, B3GALT6, CEP120, ARX, APLF, ARL13B, CALB2, HYLS1, BRCA2, BRCA1, JMJD1C, MYO1H, ATRX, PIGW, ARVCF, ARL3, LINC00327, ACTG2, TCTN2, CEP290, FANCE, GATA1, FANCF, FANCG, CC2D2A, FOXF1, SALL4, INPP5E, GJB2, PALB2, FANCI, GP1BB, RFWD3, FANCL, MKS1, BCOR, FANCB, SLC6A8, FANCD2, FANCC, TCTN1, TMEM231, CPLANE1, EP300, TMEM237, ERCC4, FANCM, FANCA, ACHE, NTRK1, SLC9A3R2, NRG3, SCAF11, GEMIN2, GFRA4, SLC2A1, SEMA3A, MCS+9.7, BMP4, DNMT3B, FN1, HOXB5, S100A1, NID1, PTCH1, MIR215, PSPN, AKT1, NLGN1, IL11, PROK1, CALCA, MIR141, ICAM1, KCNN3, ANGPTL2, ELP1, PGP, PLAGL2, ARTN, RGS6, BMP2, S100B, MECP2, BMP10, MEG3, GLI1, CX3CL1, VAMP5, MIR483, NTF3, MIR770, ACTR2, AICDA, LRSAM1, SNRNP70, CHRNE, ITIH5, DNMT1, CYP2B6, COL6A1, COL6A2, DECR1, CTH, DCX, DVL2, ITPKC, ESR1, GFRA2, IARS2, GABRG2, ACKR3, FHL1, FGF1, NLGN2, FABP7, ERCC1, DNTT, ENO2, NOX5, EDNRA, DYRK1A, DVL3, DVL1, SVEP1, DUSP6, KCNG4, ZNF827, CDX2, MIR192, MIR214, ADRA2B, MIR24-1, MIR30A, MIR31, ADRA1A, MIR31HG, MIR431, MIR488, COL6A4P2, MIR637, MIR939, C17orf107, MIR1324, HOTTIP, MTRNR2L12, ADARB1, ACTB, FALEC, LINC01844, CBSL, ALK, MIR150, CDX1, MIR146A, TSGA13, CD34, CCK, PROKR2, CBS, GPR42, CAV1, CASR, KCNG3, NLRP6, CAPN1, BRS3, DOK6, BMP5, FGD2, BBS2, ASS1, CCDC66, COL6A4P1, RBPMS2, APP, GLI3, FOXA1, GRB10, WNT8A, CXCR4, MAPK10, DPF3, MAPK3, DVL1P1, PRKCI, FXYD1, CUL3, PLEK, IL1RL2, BANF1, HSPB3, PLAG1, LPAR2, DCLK1, KLF4, PIK3CG, SLIT2, HAND2, ROCK2, PIGA, TUBA1A, WNT1, ANO1, VIP, SCN1B, SCN10A, SIM2, RYR3, RYR2, RYR1, SOX2, SOX4, SOX9, ROCK1, SRY, SSTR4, STC1, SYP, ROBO1, RBP4, TCOF1, RBP3, TTF1, PTPRR, PTGER2, PTGES, PCDH9, PAX6, PCDHA9, IL17RA, BACE2, IL17A, AUTS2, IGF2, IGF1, SIGLEC8, CNTN6, HSPB2, HSPB1, TLX3, KCNK4, HOXA13, MNX1, SUFU, CNTN5, NLGN3, SLC6A20, GSTT1, GSTP1, GSTM1, ITGB2, JAG2, UBR4, CXCR6, EIF4A3, NUP98, ARNT2, NOTCH1, AKT3, NOS2, NOS1, NGF, MT1A, TRAF3IP2, KCNH2, MCC, MAP2, PRDX3, STMN2, INMT, ZNF609, SMAD1, PLCB1, KCNJ12, ABO

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Description

The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid. Total colonic aganglionosis and total intestinal HSCR also occur (Amiel et al., 2008).

Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance (Amiel et al., 2008).

For a general description and a discussion of genetic heterogeneity of Hirschsprung disease (HSCR), see 142623.

Mapping

In HSCR families enriched for long-segment HSCR (L-HSCR), the major gene underlying the phenotype is RET (164761), which maps to chromosome 10q11. To elucidate the complex inheritance of the much more common short-segment HSCR (S-HSCR), Bolk Gabriel et al. (2002) conducted a genome screen in 49 affected families ascertained through a proband with S-HSCR using 371 tandem repeat polymorphisms at a map resolution of approximately 10 cM. Using allele-sharing linkage analysis, Bolk Gabriel et al. (2002) identified a region of linkage on chromosome 10q11 that was shown to represent RET. They also identified regions of linkage on chromosome 3p21 (HSCR6) between markers D3S2408 and D3S1766 (Z = 3.46, P = 1.9 x 10(-4)), and on chromosome 19q12 (see HSCR7, 606875). Coding sequence mutations in RET were present in only 40% of linked families, suggesting the importance of noncoding variation. Bolk Gabriel et al. (2002) concluded that the actions of these 3 loci seemed to be necessary and sufficient for S-HSCR, and that these 3 loci seemed to act in all families.

Garcia-Barcelo et al. (2008) provided additional evidence for the HSCR6 susceptibility locus on chromosome 3p21 in a Chinese population. A 5-SNP haplotype (CCTAT) spanning a 118-kb gene-rich region on chromosome 3p21 was found to be undertransmitted to affected offspring in 58 Chinese patient-parent trios. The association was replicated in an independent sample of 172 Chinese S-HSCR patients and 153 unrelated Chinese controls. The data suggested that a HSCR locus could lie within this region, but Garcia-Barcelo et al. (2008) acknowledged that the statistical significance of their findings did not survive rigorous multiple-testing adjustments.