Supplementary materials in support of the thesis "Methods to identify novel disease genes and uplift diagnosis rates in rare diseases"

Seaby, Eleanor and Seaby, Eleanor Grace (2023) Supplementary materials in support of the thesis "Methods to identify novel disease genes and uplift diagnosis rates in rare diseases". University of Southampton doi:10.5258/SOTON/D2910 [Dataset]

Record type: Dataset

Abstract

This dataset supports the thesis entitled "Methods to identify novel disease genes and uplift diagnosis rates in rare diseases" AWARDED BY: Univeristy of Southampton DATE OF AWARD: 2023 This dataset contains: 1. Folder called 'Appendix papers' This contains 15 published articles in peer review journals or preprint archives which represent work from my thesis. Appendix Paper 1 | Strategies to Uplift Novel Mendelian Gene Discovery for Improved Clinical Outcomes Appendix Paper 2 | Challenges in the diagnosis and discovery of rare genetic disorders using contemporary sequencing technologies Appendix Paper 3 | The mutational constraint spectrum quantified from variation in 141,456 humans Appendix Paper 4 | Transcript expression-aware annotation improves rare variant interpretation Appendix Paper 5 | Addendum: The mutational constraint spectrum quantified from variation in 141,456 humans Appendix Paper 6 | Advanced variant classification framework reduces the false positive rate of predicted loss of function (pLoF) variants in population sequencing data Appendix Paper 7 | A gene-to-patient approach uplifts novel disease gene discovery and identifies 18 putative novel disease genes Appendix Paper 8 | Response to Ramos et al. Appendix Paper 9 | 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report Appendix Paper 10 | Loss-of-function variants in TAF4 are associated with a neurodevelopmental disorder. Human Mutation Appendix Paper 11 | Monogenic de novo variants in DDX17 cause a novel neurodevelopmental disorder Appendix Paper 12 | Targeting de novo loss of function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project Appendix Paper 13 | A gene pathogenicity tool ‘GenePy’ identifies missed biallelic diagnoses in the 100,000 Genomes Project Appendix Paper 14 | A panel-agnostic strategy ‘HiPPo’ improves diagnostic efficiency in the UK 2 Genome Medicine Service Appendix Paper 15 | A novel variant in GATM causes idiopathic renal Fanconi syndrome and predicts progression to end-stage kidney disease 2. Folder called 'Supplementary Datasets' All data can be opened using Microsoft Excel. Supplementary Dataset SD1 | Enriched biological processes in DDX17 RNA-seq data [Co-author Cyril F. Bourgeois; University of Lyon] Supplementary Dataset SD2 | Curation of pLoF variants in haploinsufficient genes Supplementary Dataset SD3 | Curation of 3362 homozygous pLoF variants [Co-authors Moriel Singer-Berk, Eleina England; Broad Institute of MIT and Harvard] Supplementary Dataset SD4 | Detailed phenotype table of patients with DDX17 variants Supplementary Dataset SD5 | Differentially expressed genes in DDX17-KD cells compared to control cells [Co-author Cyril F. Bourgeois; University of Lyon] Supplementary Dataset SD6 | Detailed phenotype table of patients with HDLBP variants Supplementary Dataset SD7 | Manual curation of 45 remaining variants [Co-author N. Simon Thomas, University of Southampton] Supplementary Dataset SD8 | Re-analysis of DeNovoLOEUF on 100,000 Genomes Project data Supplementary Dataset SD9 | 36 possible missed diagnoses in patients with a cardiomyopathy phenotype Supplementary Dataset SD10 | Genes associated with cardiomyopathies Supplementary Dataset SD11 | Autosomal recessive disease genes Supplementary Dataset SD12 | 682 participants with a potential missed diagnosis Supplementary Dataset SD13 | Variants identified using the HiPPo protocol 3. Folder called 'Supplementary Tables' All data can be opened using Microsoft Excel. Supplementary Table S1 | Environmental tools in GEL Supplementary Table S2 | List of 1,815 genes tolerant of homozygous loss-of-function variation [Co-author Moriel Singer-Berk; Broad Institute of MIT and Harvard] Supplementary Table S3 | Genes tolerant of homozygous loss-of-function variation with an OMIM dominant association Supplementary Table S4 | 27 genes with more than one Genomics England kindred affected Supplementary Table S5 | 99 Class 2 and Class 3 genes Supplementary Table S6 | Sequences of siRNAs against DDX17 [Co-author Cyril F. Bourgeois; University of Lyon] Supplementary Table S7 | A summary of high-level phenotypes of the 100,000 Genomes Project patient population Supplementary Table S8 | All human genes curated with a LOEUF score Supplementary Table S9 | 182 participants without a listed cardiomyopathy phenotype that had a pathogenic variant returned by 100KGP in a cardiomyopathy-related gene Supplementary Table S10 | Quality control of 24 samples from 8 families undergoing parallel research exome and clinical genome [Co-author Nichola Grahame; University of Southampton] 4. Folder called 'Supplementary Figures' Contains a single word document will the following figures: Supplementary Figure S1 | Crispr/Cas9 microinjection into X. tropicalis eggs produces mosaic homozygous crispant tadpoles encoding truncated Ddx17 which is inherited in the F1 generation [Co-authors Annie Godwin, Matt Guille; University of Portsmouth] Supplementary Figure S2 | The amino acid alignment between the H. sapiens and X. tropicalis Ddx17 proteins [Co-authors Annie Godwin, Matt Guille; University of Portsmouth] Supplementary Figure S3 | F0 mosaic homozygous X. tropicalis display reduced axon outgrowth, and working memory like F1 models, but also gastrulation defects and short term microcephaly [Co-authors Annie Godwin, Matt Guille] Supplementary Figure S4 | Results of dark-light transitions assay and neuronal outgrowth [Co-authors Annie Godwin, Matt Guille; University of Portsmouth] Supplementary Figure S5 | Compound heterozygous ddx17-/- tadpoles are morphologically normal but show working memory deficits [Co-authors Annie Godwin, Matt Guille; University of Portsmouth] Supplementary Figure S6 | Network representation of the top 40 enriched biological processes [Co-author Cyril F. Bourgeois; University of Lyon] Supplementary Figure S7 | Enriched biological processes for down-regulated and up-regulated genes [Co-author Cyril F. Bourgeois; University of Lyon]