Patients with a classical or attenuated form of FAP for whom no mutations in the APC gene have been found and whose family anamnesis suggests an autosomal recessive pattern of inheritance.
Adenomatous Polyposis coli, MAP - MUTYH
MUTYH Gene (MutY Homolog of E. coli), MYH
Clinical Features
Familial Adenomatous Polyposis (FAP) consists of two distinct forms: the classical form with more than 100 adenomatous polyps of primarily distal location and an age of onset in childhood or adolescence, and the attenuated form with between 5 and 100 (on average 30) adenomatous polyps, a milder progression and later age of onset.
In approximately 70-80% of cases of classical FAP, mutations are found in the APC gene, in contrast to the attenuated form, where mutations in the APC gene are rare.
Adenomatous Polyposis coli with mutations in the MUTYH gene (MutY Homolog of E. coli) is known as MAP (MUTYH associated polyposis). MUTYH mutations are found in 5% of cases of the classical form of FAP and in 30% of cases of the attenuated form. MAP is also generally associated with a milder phenotype with fewer adenomas and a later age of onset. However, a definite clinical differentiation of MAP and FAP is not possible. Extracolonic manifestations (congenital hypertrophy of the reticule pigment epithelium, or CHRPEs) have been described for both FAP and MAP. According to current data, desmoid tumors do not occur in conjunction with MAP.
While MAP follows an autosomal recessive pattern of inheritance, FAP is an autosomal dominant inherited disease; a molecular genetic differentiation of MAP and FAP is thus essential to determining the risk factors and the best course of treatment for patients and their families. In individual cases, MAP can, due to its low number of polyps, be considered a differential diagnosis in cases of HNPCC; since the attenuated form of FAP can clinically overlap with HNPCC syndrome, analysis of the MUTYH gene should be performed when indicated by corresponding clinical suspicion and a negative test result for HNPCC.
Genetic Information
In contrast to the dominant form of FAP, which is caused by mutations in the APC gene, the recessive MAP is the result of germ-line mutations in the MUTYH gene. The MUTYH gene has 16 coding exons, is located on chromosome 1 (1p34.1) and codes for protein 546 amino acids long that participates in DNA repair (base-excision repair system, or BER).
The two most common mutations (Tyr165Cys and Gly382Asp) are responsible for approx. 85% of all cases of MAP among Caucasians.
In addition, the literature describes approx. 15 other pathogenic mutations that span the entire encoding region of the MUTYH gene.
Prevalence
Biallelic mutations in the MUTYH gene are found (depending on family anamnesis) in up to 30% of patients suspected of having FAP and for whom no mutation in the APC gene was detected.
Diagnostic
Indication
Method
All exons in the MUTYH gene as well as their flanking regions are analysed by sequence analysis.
Deletions and/or duplications of one or more exons are captured by MLPA analysis.
Sample Requirement
2 - 4 ml of EDTA blood
Duration
4 - 6 weeks