MUTYH was first reported in relation to MUTYH-related attenuated familial adenomatous polyposis , also known as MUTYH-Associated Polyposis (MAP), by Jones S, et al (PMID: 12393807) and Al-Tassan N, et al., (PMID: 11818965) in 2002. MUTYH has been noted to be associated with both autosomal recessive and autosomal dominant MUTYH-related attenuated familial adenomatous polyposis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, this curation focuses solely on autosomal recessive MUTYH-related attenuated familial adenomatous polyposis (MONDO:0012041) due to the difference in inheritance pattern and phenotype differences. This autosomal recessive condition causes an increased risk of colorectal adenomas and colon cancer (see Nielsen et al. PMID:23035301 for clinical phenotype). At least 7 cases from Jones et al contributed homozygous truncating or missense, or compound heterozygous alleles, and Al-Tassan reported on a larger pedigree with three siblings segregating biallelic alleles consistent with recessive inheritance. A case control study by Cleary et al (PMID: 19245865, 2009) identified 27 homozygous or compound heterozygous cases (with 1 control subject carrying a homozygous variant) through a large case-control study. Through cases, segregation and case-control, the maximum score for genetic evidence has been reached (12 points) although more evidence is available in the literature. This gene-disease association is also supported by experimental evidence (5.5 points) including MUTYH colonic tissue expression (PMID:22876359, PMID:25613900), a mouse model developing colonic polyps (PMID: 17638869), biochemical function of MUTYH in base excision repair deficiency (PMID: 15199168), and MUTYH knockout in mouse ES cells disrupting DNA glycosylase activity (and base excision repair) (PMID: 12917422). In summary, MUTYH recessive variants are definitively associated (17.5 points) with MUTYH-related attenuated familial adenomatous polyposis (MONDO:0012041), also known as MUTYH-Associated Polyposis (MAP). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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