Alternative titles; symbols
ORPHA: 220460, 247798, 733; DO: 0080410;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.1 | Adenomas, multiple colorectal | 608456 | Autosomal recessive | 3 | MUTYH | 604933 |
A number sign (#) is used with this entry because of evidence that autosomal recessive familial adenomatous polyposis-2 (FAP2) is caused by homozygous or compound heterozygous mutation in the MUTYH (MYH) gene (604933) on chromosome 1p34.
Autosomal recessive colorectal adenomatous polyposis is a disorder characterized by adult-onset of multiple colorectal adenomas and adenomatous polyposis. Affected individuals have a significantly increased risk of colorectal cancer (summary by Sieber et al., 2003).
Cheadle and Sampson (2003) reviewed the molecular pathology and biochemistry of MYH colonic polyposis.
For a discussion of genetic heterogeneity of FAP, see 175100.
Autosomal recessive FAP is characterized by multiple colorectal adenomas and a high risk of colorectal cancer (summary by Sampson et al., 2003).
Clinical Variability
A combination of pilomatricomas (132600) and adenomatous polyposis coli as an autosomal recessive trait has been reported with mutation in the MYH gene (604933.0008) (Baglioni et al., 2005).
Barnetson et al. (2007) reported a patient with endometrial adenocarcinoma (see 608089) and sebaceous carcinoma of the face who was compound heterozygous for 2 common mutations in the MUTYH gene (Y165C; 604933.0001 and G382D; 604933.0002). Colonic adenomas were not reported, but a paternal aunt reportedly had colorectal cancer in her thirties. Barnetson et al. (2007) noted that the phenotype associated with biallelic MUTYH mutations may include extracolonic manifestations, including endometrial cancer and sebaceous carcinoma, as seen in other inherited colorectal cancer syndromes such as Muir-Torre syndrome (158320) and Lynch syndrome (120435).
Among 614 families recorded in 6 regional registers of polyposis in the UK, Sampson et al. (2003) identified 111 with neither dominant transmission nor evidence of APC mutation. Molecular genetic analysis showed that 25 had biallelic mutations of the MYH gene. The data showed that MYH polyposis can be transmitted as an autosomal recessive trait, requiring a change in genetic counseling, testing, and surveillance. Sampson et al. (2003) recommended that genetic analysis of MYH be offered to patients with a phenotype resembling FAP or attenuated FAP when no clear evidence of vertical transmission is recorded. Further studies were considered necessary to clarify the risk of colorectal cancer for MYH heterozygous individuals.
Al-Tassan et al. (2002) studied a British family in which 3 sibs had multiple colorectal adenomas and carcinoma. There was no clear pathogenic change in the APC gene. Analysis of the MYH gene showed that the sibs were compound heterozygous for nonconservative missense variants (604933.0001-604933.0002).
Jones et al. (2002) and Sieber et al. (2003) also identified biallelic MYH mutations in patients with multiple colorectal adenomas.
Rouleau et al. (2011) reported a 45-year-old French man who was found to have 25 colorectal adenomas on colonoscopy. He had no family history of the disorder. Analysis of the APC gene was negative, and molecular analysis identified compound heterozygosity for mutations in the MUTYH gene: a missense mutation (604933.0002) and a large rearrangement resulting in the deletion of exons 3 to 16 (604933.0009).
Al-Tassan, N., Chmiel, N. H., Maynard, J., Fleming, N., Livingston, A. L., Williams, G. T., Hodges, A. K., Davies, D. R., David, S. S., Sampson, J. R., Cheadle, J. P. Inherited variants of MYH associated with somatic G:C-T:A mutations in colorectal tumors. Nature Genet. 30: 227-232, 2002. [PubMed: 11818965] [Full Text: https://doi.org/10.1038/ng828]
Baglioni, S., Melean, G., Gensini, F., Santucci, M., Scatizzi, M., Papi, L., Genuardi, M. A kindred with MYH-associated polyposis and pilomatricomas. Am. J. Med. Genet. 134A: 212-214, 2005. [PubMed: 15690400] [Full Text: https://doi.org/10.1002/ajmg.a.30585]
Barnetson, R. A., Devlin, L., Miller, J., Farrington, S. M., Slater, S., Drake, A. C., Campbell, H., Dunlop, M. G., Porteous, M. E. Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer. Clin. Genet. 72: 551-555, 2007. [PubMed: 17956577] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00900.x]
Cheadle, J. P., Sampson, J. R. Exposing the MYtH about base excision repair and human inherited disease. Hum. Molec. Genet. 12: R159-R165, 2003. [PubMed: 12915454] [Full Text: https://doi.org/10.1093/hmg/ddg259]
Jones, S., Emmerson, P., Maynard, J., Best, J. M., Jordan, S., Williams, G. T., Sampson, J. R., Cheadle, J. P. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-to-T:A mutations. Hum. Molec. Genet. 11: 2961-2967, 2002. [PubMed: 12393807] [Full Text: https://doi.org/10.1093/hmg/11.23.2961]
Rouleau, E., Zattara, H., Lefol, C., Noguchi, T., Briaux, A., Buecher, B., Bourdon, V., Sobol, H., Lidereau, R., Olschwang, S. First large rearrangement in the MUTYH gene and attenuated familial adenomatous polyposis syndrome. (Letter) Clin. Genet. 80: 301-303, 2011. [PubMed: 21815886] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01699.x]
Sampson, J. R., Dolwani, S., Jones, S., Eccles, D., Ellis, A., Evans, D. G., Frayling, I., Jordan, S., Maher, E. R., Mak, T., Maynard, J., Pigatto, F., Shaw, J., Cheadle, J. P. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 362: 39-41, 2003. [PubMed: 12853198] [Full Text: https://doi.org/10.1016/S0140-6736(03)13805-6]
Sieber, O. M., Lipton, L., Crabtree, M., Heinimann, K., Fidalgo, P., Phillips, R. K. S., Bisgaard, M.-L., Orntoft, T. F., Aaltonen, L. A., Hodgson, S. V., Thomas, H. J. W., Tomlinson, I. P. M. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. New Eng. J. Med. 348: 791-799, 2003. [PubMed: 12606733] [Full Text: https://doi.org/10.1056/NEJMoa025283]