Breakpoint characterization of a novel large intragenic deletion of MUTYH detected in a MAP patient: Case report

We have identified a large deletion in the MUTYH gene: a > 4.2 kb deletion encompassing exons 4-16. This is the second description of this rearrangement, which has been recently described as the first large deletion in this gene. The clinically suspected MAP patient was homozygous for this mutation and presented with no amplification products for 14 exons of MUTYH on initial screening. Deletion breakpoints were refined to base pair level through array comparative genomic hybridization (aCGH) analysis followed by sequencing. The identified breakpoints were located within intron 3 and 146 bp downstream of the 3' end of the gene, with the presence of an AluJr element adjacent to the distal breakpoint. The presence of a 2 bp insertion at the junction suggests the involvement of the non-homologous end joining (NHEJ) repair mechanism, possibly facilitated by rearrangement-promoting elements. Examination of the MUTYH locus revealed a high Alu density that may make this region prone to rearrangements.Large deletions are a possible mechanism for loss of function of the MUTYH gene, and investigation of such mutations may be important in identifying causative mutations in MAP patients.MUTYH-associated polyposis (MAP) (MIM#608456), a recessive inherited syndrome characterized by colorectal adenomatous polyposis and a high risk of colorectal cancer, is a disorder caused by biallelic pathogenic germline variants in the human mutY homologue (MUTYH) gene [1]. MUTYH spans 11.2 kb on chromosome 1p34.1 [2] and encodes a DNA glycosylase that plays a key role in base excision repair (BER) of 8-oxoG:A mismatches by removing the mismatched adenine [3]. The oxidation product 8-oxoG is the most stable product of oxidative DNA damage [4], which can lead to G:C to T:A transversions if not repaired5. Tumorigenesis in MAP patients is thought to be initiated by somatic G:C →T:A transversions in KRAS and/or APC [5].The clinical manifestations of MAP resemble familial adenomatous polyposis (FAP; M