Quantitative changes in gene expression caused by missense variants in deoxyribonucleic acid repair genes

Inherited mutations in DNA repair genes are major contributors to familial cancer syndromes. Most pathogenic mutations introduce premature stop codons resulting in the loss of protein function. Missense variants of uncertain pathogenic significance are also often observed. In an attempt to understand the physiological attributes of this category of variants, this thesis analysed two recurrent coding variants using a multi-disciplinary approach. The first variant, PMS2 c.2002A>G, was identified in the Inuit population of Quebec and early onset cancers co-segregate with homozygous status. The second, BRCA2 c.6853A>G, appears to be restricted to the Ashkenazi Jewish population and is frequently recorded in the database of Breast Cancer Information Core (BIC, http://research.nhgri.nih.gov/bic/). Both variants not only cause the substitution of an isoleucine to a valine in the proteins, but also interfere with RNA splicing. The variant PMS2 c.2002 A>G creates a novel 5' splicing site which competes with the authentic one, resulting in biased gene expression. The majority of the transcripts are aberrant ones with a five-base pair deletion and a minority of intact transcripts are still produced. The intact transcripts are translated into a full-length proteins which contribute to the milder phenotype associated with this variant, when compared to phenotypes caused by homozygous truncating PMS2 mutations. The variant BRCA2 c.6853A>G disrupts a splicing enhancer promoting the skipping of exon 12, an in-frame exon that does not code for any known functional domains. No detectable phenotype is caused by this variant.The work described in this thesis generated significant medical insights into hereditary syndrome. First, we demonstrated that the inclusion of expression analysis in gene test can improve the accuracy of predicting the functional significance of a candidate variant. Second, manipulating gene expression may be a potential avenue of preventing recessive diseases. Finally, phenotypic variation may be caused by multiple factors, so predicting disease risk solely based on DNA sequence should be practised cautiously with full awareness of the limitation.

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