DOI: 10.5258/soton/d2910
title: Supplementary materials in support of the thesis "Methods to identify novel disease genes and uplift diagnosis rates in rare diseases"

description: 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]