Common genetic variation and spliceosome variants in rare developmental disorders
type: CreativeWork
description: Although thousands of rare disorders are caused by single, deleterious, protein- coding variants, evidence suggests that common variants also contribute to risk for rare, neurodevelopmental disorders (NDDs). These are likely affecting the penetrance of protein-coding variants as well as expressivity, posing a major challenge in the interpretation of rare variants. An additional challenge is our incomplete understanding of which variants are likely to affect gene function. Due to the high burden of “variants of unknown significance” (VUS), there is a great need to develop molecular biomarkers of individual disorders which could be used as an intermediate phenotype to help determine whether a VUS is pathogenic or benign. For disorders which are due to mutations in spliceosomal components, global patterns of splicing changes may be a useful biomarker. The research presented falls into three main projects. First, I investigated via genetically-predicted gene expression, whether cis-regulatory variants modify the penetrance of inherited, putatively damaging variants in NDD probands in the Deciphering Developmental Disorders (DDD) Study. To determine whether there were overall differences in predicted gene expression between probands and controls, I conducted a Transcriptome Association Study. I then tested whether the predicted gene expression of genes harbouring inherited, putatively damaging variants, is lower in undiagnosed NDD probands compared to controls. Finally, I investigated the modified penetrance of inherited, putatively damaging variants by comparing predicted gene expression between undiagnosed NDD probands and their unaffected, variant-transmitting parents. Second, I further explored the role of common variants in severe NDDs using polygenic scores (PGS) in both DDD and the Genomics England (GEL) 100,000 Genomes project. I tested whether undiagnosed NDD probands over- or under- inherit PGS for NDDs and correlated traits. I found that NDD probands over-inhe…
abstract: Although thousands of rare disorders are caused by single, deleterious, protein- coding variants, evidence suggests that common variants also contribute to risk for rare, neurodevelopmental disorders (NDDs). These are likely affecting the penetrance of protein-coding variants as well as expressivity, posing a major challenge in the interpretation of rare variants. An additional challenge is our incomplete understanding of which variants are likely to affect gene function. Due to the high burden of “variants of unknown significance” (VUS), there is a great need to develop molecular biomarkers of individual disorders which could be used as an intermediate phenotype to help determine whether a VUS is pathogenic or benign. For disorders which are due to mutations in spliceosomal components, global patterns of splicing changes may be a useful biomarker. The research presented falls into three main projects. First, I investigated via genetically-predicted gene expression, whether cis-regulatory variants modify the penetrance of inherited, putatively damaging variants in NDD probands in the Deciphering Developmental Disorders (DDD) Study. To determine whether there were overall differences in predicted gene expression between probands and controls, I conducted a Transcriptome Association Study. I then tested whether the predicted gene expression of genes harbouring inherited, putatively damaging variants, is lower in undiagnosed NDD probands compared to controls. Finally, I investigated the modified penetrance of inherited, putatively damaging variants by comparing predicted gene expression between undiagnosed NDD probands and their unaffected, variant-transmitting parents. Second, I further explored the role of common variants in severe NDDs using polygenic scores (PGS) in both DDD and the Genomics England (GEL) 100,000 Genomes project. I tested whether undiagnosed NDD probands over- or under- inherit PGS for NDDs and correlated traits. I found that NDD probands over-inhe…
author: Wigdor, Emilie
language: eng
keywords: cis-regulatory variants, common genetic variation, complex traits, eQTL, genetics, incomplete penetrance, modified penetrance, polygenic scores, rare disease, rare disorders, RNA-sequencing, spliceosome, splicing, TWAS
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2022-09-29
date modified: 2026-07-22T22:24:18Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.91369