Using whole exome and genome sequencing data to identify novel genes predisposing to colorectal polyposis

Houseman, Amy 2025. Using whole exome and genome sequencing data to identify novel genes predisposing to colorectal polyposis. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Colorectal polyposis is characterised by the development of multiple polyps in the colon and rectum, which can lead to colorectal cancer if left unmonitored. While several inherited colorectal polyposis syndromes have been identified, many cases remain of an unknown genetic basis. This thesis aims to identify novel predisposition genes for colorectal polyposis using whole-exome and genome sequencing data from patients with no known genetic cause for their colorectal polyposis. Method A cohort of 226 unrelated individuals with colorectal polyposis, all previously testing negative for germline mutations in APC and MUTYH, was analysed. Index cases included 104 participants from the Genetic Mechanisms in Polyposis of the Bowel study and 122 from the 100,000 Genomes Project (100kGP). Participants underwent whole exome sequencing (WES) or whole genome sequencing (WGS). WES variants were called and annotated using a custom bioinformatics pipeline. WGS variants were obtained via the 100kGP pipeline. Variant sets (including single-nucleotide variants and insertions or deletions) were merged and filtered to retain rare, predicted-damaging variants. Known polyposis-associated genes were first assessed. Novel candidate genes were defined as those with variants in two or more unrelated cases under either of two models: (i) an autosomal recessive model with subsequent exclusion of genes where biallelic loss of function (LOF) variants are tolerated (i.e. found in healthy controls), and, (ii) an autosomal dominant heterozygous LOF model with subsequent exclusion of genes that tolerate LOF based upon GnomAD loss-of-function observed/expected upper bound fraction (LOEUF) scores >0.35. Results After filtering, 27,546 variants were retained. Pathogenic variants were identified in APC (four cases), MUTYH, MBD4, AXIN2, and POLE. Under the recessive model, 68 genes were flagged, but none passed quality control. Under a heterozygous LOF model, 1303 genes were potential candidates, but only one novel gene, BCL9L, was intolerant to LOF variants and passed quality control. Two families had LOF variants in BCL9L, and six additional cases were found in the 100kGP, all upstream of the last exon. Tumours with two BCL9L mutations had significantly fewer APC mutations (35%, P<1×10⁻⁴), suggesting an alternative, novel, APC-independent mechanism of tumourigenesis. Conclusion Monogenic colorectal polyposis traits attributable to novel genes are likely to be very rare. However, BCL9L has emerged as a promising candidate gene and warrants further investigation.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	16 March 2026
Last Modified:	16 Mar 2026 16:16
URI:	https://orca.cardiff.ac.uk/id/eprint/185797

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