MUTYH‐associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype

Abstract

To determine the frequency, mutation spectrum and phenotype of the recently described autosomal recessive MUTYH-associated polyposis (MAP), we performed a systematic search for MUTYH (MYH) mutations by sequencing the complete coding region of the gene in 329 unselected APC mutation-negative index patients with the clinical diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP (AFAP). Biallelic germline mutations in MUTYH were identified in 55 of the 329 unselected patients (17%) and in another 9 selected index cases. About one-fifth (20%) of the 64 unrelated MAP patients harboured none of the 2 hot-spot missense mutations Y165C and/or G382D. Including 7 affected relatives, almost all MAP patients presented with either an attenuated (80%) or with an atypical phenotype (18%). Fifty percentage of the MAP patients had colorectal cancer at diagnosis. Duodenal polyposis was found in 18%, thyroid and stomach cancer in 1 case, other extraintestinal manifestations associated with FAP were not observed. In 8 families, vertical segregation was suspected; in 2 of these families, biallelic mutations were identified in 2 generations. Monoallelic changes with predicted functional relevance were found in 0.9% of the 329 patients, which is in accordance with the carrier frequency in the general population. In conclusion, biallelic MUTYH mutations are the underlying genetic basis in a substantial fraction of patients with adenomatous polyposis. The phenotype of MAP is best characterised as attenuated or atypical, respectively. Colorectal surveillance starting at about 18 years of age is recommended for biallelic mutation carriers and siblings of MAP patients, who refuse predictive testing. ' 2006 Wiley-Liss, Inc.

MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events

“…Considering the general late onset of both adenoma and CRC formation in MAP patients, 4,6,8,11,23 negative selection would be expected to be limited. Nevertheless, a robust correlation between certain MUTYH genotypes and the colorectal phenotype has recently been established.…”

Clinical utility gene card for: MUTYH-associated polyposis (MAP), Autosomal recessive colorectal adenomatous polyposis, Multiple colorectal adenomas, Multiple adenomatous polyps (MAP) - update 2012

“…However, using this method a considerable proportion (up to 20%) of biallelic mutation carriers is missed. 2 Screening for large deletions and duplications with MLPA or other methods for gene dosage analysis can be considered, but is currently not generally recommended as routine diagnostic approach due to the very low frequency of this mutation type.…”

“…1 Broad, all types of point mutations (missense, splice site, and truncating mutations). [2][3][4][5] Mutations were described in almost all exons (except exons 1 and 2). Gross genomic deletions or duplications seem to be very rare events, only one recurrent large deletion has been described so far.…”

S3-Leitlinie – Kolorektales Karzinom

“…Der kolorektale Phänotyp der MAP ähnelt dem der AFAP: Meist treten zwischen 20 und einigen hundert Adenomen auf, das mittlere Diagnosealter ist 45 Jahre (Streuung 12 -68 Jahre) [267]. Unbehandelt beträgt das KRK-Lebenszeitrisiko etwa 70 -80 % [268].…”