ORPHA: 388;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.32 | {Hirschsprung disease, susceptibility to, 4} | 613712 | Autosomal dominant | 3 | EDN3 | 131242 |
A number sign (#) is used with this entry because of evidence that susceptibility to Hirschsprung disease (HSCR4) is associated with variation in the EDN3 gene (131242) on chromosome 20q13.
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 discussion of genetic heterogeneity of susceptibility to Hirschsprung disease, see 142623.
Bidaud et al. (1997) reported a sporadic case of isolated Hirschsprung disease with a heterozygous EDN3 missense mutation (131242.0004). The findings gave support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggested the possibility that either recessive or weakly penetrant dominant alleles can occur at the EDN3 locus, depending on the nature of the mutation.
In a patient with short-segment Hirschsprung disease without any Waardenburg features, Svensson et al. (1999) found a novel heterozygous frameshift mutation (131242.0006), which was predicted to result in haploinsufficiency.
Sanchez-Mejias et al. (2010) screened the EDN3 and EDNRB (131244) genes in 196 patients with Hirschsprung disease from Spain using high performance liquid chromatography. They detected 11 sequence variants in the EDN3 gene among the patients, including 4 novel variants. They also found novel mutations in the EDNRB gene, including a truncating mutation (see 131244.0009) in an alternative isoform.
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]
Bidaud, C., Salomon, R., Van Camp, G., Pelet, A., Attie, T., Eng, C., Bonduelle, M., Amiel, J., Nihoul-Fekete, C., Willems, P. J., Munnich, A., Lyonnet, S. Endothelin-3 gene mutations in isolated and syndromic Hirschsprung disease. Europ. J. Hum. Genet. 5: 247-251, 1997. [PubMed: 9359047]
Hirschsprung, H. Stuhltragheit Neugeborener in Folge von Dilatation und Hypertrophie des Colons. Jahrb. Kinderheilk. 27: 1-7, 1888.
Sanchez-Mejias, A., Fernandez, R. M., Lopez-Alonso, M., Antinolo, G., Borrego, S. New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. Genet. Med. 12: 39-43, 2010. [PubMed: 20009762] [Full Text: https://doi.org/10.1097/GIM.0b013e3181c371b0]
Svensson, P.-J., Von Tell, D., Molander, M.-L., Anvret, M., Nordenskjold, A. A heterozygous frameshift mutation in the endothelin-3 (EDN-3) gene in isolated Hirschsprung's disease. Pediat. Res. 45: 714-717, 1999. [PubMed: 10231870] [Full Text: https://doi.org/10.1203/00006450-199905010-00018]