Non-Coding Aberrations in Mismatch Repair Genes Underlie a Substantial Part of the Missing Heritability in Lynch Syndrome

Explore the latest research on Lynch syndrome and mismatch repair genes in this 29-minute webinar presented by Dr. Richarda De Voer, assistant professor at Radboud University Medical Centre. Delve into the genetic predisposition for early-onset colorectal and endometrial cancers, focusing on non-coding aberrations in mismatch repair genes. Learn about current diagnostic techniques, the role of somatic mutations, and the application of targeted long-read sequencing in identifying unexplained cases. Gain insights into functional testing methods for validating pathogenicity of non-coding aberrations. Understand the implications of this research for improving Lynch syndrome diagnosis and uncovering the missing heritability in unexplained cases.

Intro
Learning objectives
Outline
Hereditary colorectal cancer & polyposis syndromes
Mendelian colorectal cancer & polyposis syndromes
What is Lynch syndrome?
Mismatch repair machinery
Current diagnostic route for detection of Lynch syndrome
Analysis of germline and somatic coding aberrations in MMR genes
The majority of unexplained dMMR tumours have two somatic MMR mutations
Individuals with somatic dMMR have a higher age at diagnosis compared to LS patients
Some individuals with unexplained dMMR ("Lynch-like" syndrome) have clear family histories
Design of targeted long-read sequencing of MMR genes
Targeted long-read sequencing allows for the detection of SNV, small indels, exon deletions and Alu insertions
Targeted long-read MMR gene sequencing of individuals with Lynch-like syndrome
Non-coding aberrations in MMR genes functionally tested in mini- gene and promoter assays to validate pathogenicity
What can be the consequence of a deep intronic donor site introduction?
Functional analysis by use of a mini-gene splice assay
Noncoding aberrations in MMR genes functionally tested in mini- gene and promoter assays to validate pathogenicity
Noncoding aberrations in MMR genes functionally tested in mini-gene and promoter assays to validate pathogenicity
Summary & Future perspective