Cytogenetic location: 19q12 Genomic coordinates (GRCh38) : 19:28,100,001-31,900,000
| Location | Phenotype | Inheritance |
Phenotype mapping key |
Phenotype MIM number |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21 | {Hirschsprung disease, susceptibility to, 6} | 2 | 606874 | HSCR6 | 606874 | |
| 4q31.3-q32.3 | {Hirschsprung disease, susceptibility to, 9} | 2 | 611644 | HSCR9 | 611644 | |
| 5p13.2 | {Hirschsprung disease, susceptibility to, 3} | AD | 3 | 613711 | GDNF | 600837 |
| 9q31 | {Hirschsprung disease, susceptibility to, 5} | AD | 2 | 600156 | HSCR5 | 600156 |
| 10q11.21 | {Hirschsprung disease, protection against} | AD | 3 | 142623 | RET | 164761 |
| 10q11.21 | {Hirschsprung disease, susceptibility to, 1} | AD | 3 | 142623 | RET | 164761 |
| 13q22.3 | {Hirschsprung disease, susceptibility to, 2} | AD | 3 | 600155 | EDNRB | 131244 |
| 16q23 | {Hirschsprung disease, susceptibility to, 8} | 2 | 608462 | HSCR8 | 608462 | |
| 19q12 | {Hirschsprung disease, susceptibility to, 7} | 2 | 606875 | HSCR7 | 606875 | |
| 20q13.32 | {Hirschsprung disease, susceptibility to, 4} | AD | 3 | 613712 | EDN3 | 131242 |
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.
In HSCR families enriched for long-segment HSCR (L-HSCR), the major gene underlying the phenotype is RET (164761). 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 19q12 (HSCR7) between markers D19S1037 and D19S587 (Z = 3.23, P = 6.6 x 10(-4)) and on chromosome 3p21 (see HSCR6, 606874). 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 23 loci seemed to act in all families.
Amiel, J., Sproat-Emison, E., Garcia-Barceo, M., Lantieri, F., Burzynski, G., Borrego, S., Pelet, A., Arnold, S., Miao, X., Griseri, P., Brooks, A. S., Antinolo, G., and 12 others. Hirschsprung disease: associated syndromes and genetics: a review. J. Med. Genet. 45: 1-14, 2008. [PubMed: 17965226, related citations] [Full Text]
Bolk Gabriel, S., Salomon, R., Pelet, A., Angrist, M., Amiel, J., Fornage, M., Attie-Bitach, T., Olson, J. M., Hofstra, R., Buys, C., Steffann, J., Munnich, A., Lyonnet, S., Chakravarti, A. Segregation at three loci explains familial and population risk in Hirschsprung disease. Nature Genet. 31: 89-93, 2002. [PubMed: 11953745, related citations] [Full Text]
Hirschsprung, H. Stuhltragheit Neugeborener in Folge von Dilatation und Hypertrophie des Colons. Jahrb. Kinderheilk. 27: 1-7, 1888.
ORPHA: 388; DO: 10487;
Cytogenetic location: 19q12 Genomic coordinates (GRCh38) : 19:28,100,001-31,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q12 | {Hirschsprung disease, susceptibility to, 7} | 606875 | 2 |
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.
In HSCR families enriched for long-segment HSCR (L-HSCR), the major gene underlying the phenotype is RET (164761). 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 19q12 (HSCR7) between markers D19S1037 and D19S587 (Z = 3.23, P = 6.6 x 10(-4)) and on chromosome 3p21 (see HSCR6, 606874). 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 23 loci seemed to act in all families.
Amiel, J., Sproat-Emison, E., Garcia-Barceo, M., Lantieri, F., Burzynski, G., Borrego, S., Pelet, A., Arnold, S., Miao, X., Griseri, P., Brooks, A. S., Antinolo, G., and 12 others. Hirschsprung disease: associated syndromes and genetics: a review. J. Med. Genet. 45: 1-14, 2008. [PubMed: 17965226] [Full Text: https://doi.org/10.1136/jmg.2007.053959]
Bolk Gabriel, S., Salomon, R., Pelet, A., Angrist, M., Amiel, J., Fornage, M., Attie-Bitach, T., Olson, J. M., Hofstra, R., Buys, C., Steffann, J., Munnich, A., Lyonnet, S., Chakravarti, A. Segregation at three loci explains familial and population risk in Hirschsprung disease. Nature Genet. 31: 89-93, 2002. [PubMed: 11953745] [Full Text: https://doi.org/10.1038/ng868]
Hirschsprung, H. Stuhltragheit Neugeborener in Folge von Dilatation und Hypertrophie des Colons. Jahrb. Kinderheilk. 27: 1-7, 1888.
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