Developmental Disorders: From Diagnosis to Mechanism via Cis-Regulation
Lead Research Organisation:
University of Edinburgh
Department Name: UNLISTED
Abstract
The FitzPatrick group use DNA sequencing technologies and advanced analytics to understand the causes of severe diseases affecting babies and children. They are particularly focussed on two groups of diseases. Firstly severe birth defects affecting both eyes (missing eyes, very small eyes, structurally abnormal eyes). The other group is children with severe intellectual disability and poor growth. They wish to understand how and why these disorders occur “out of the blue” and what are the underlying problems that occur to cells during development that results in the problems that are apparent at birth.
Technical Summary
Our research group, led by David FitzPatrick, an academic paediatric geneticist, focuses on understanding the genetic basis of severe developmental disorders Major aims are identification of genetic causes of major eye malformations and a severe intellectual disability syndrome; Cornelia de Lange syndrome (CdLS). Following their discovery that a major cause of severe bilateral eye malformations is de novo formation of heterozygous, loss-of-function mutations in SOX2, they have used exome sequencing to identify several novel loci such as YAP1 and MAB21L2 for severe bilateral coloboma. They have also identified genetic changes in BRD4 as a novel cause of CdLS. A common theme of this work is the innovative use of genetic technologies to identify and validate causative mutations affecting the structure or regulation of individual genes. The major focus of the future work is the use of whole genome sequencing and cell and animal models to understand the impact of genetic changes in enhancers of dosage sensitive transcription factors in developmental disease. We have 3 major aims as follows:
1) Identify and categorise highly penetrant genomic mutations causing human eye malformations using family-based whole genome sequencing (WGS) and whole exome sequencing (WES) with particular focus on interpreting changes in the noncoding genome
2) Develop broadly applicable approaches to integrate the available clinical genomic data with quantitative (growth, developmental milestones) and categorical (HPO terms) phenotypic features to improve the diagnosis of known diseases and the discovery of new genes/genetic mechanisms.
3) Define the functional genomic characteristics of the transitions in gene regulatory networks (GRN) driving very early eye development using in vitro (human embryonic stem cells differentiation) and in vivo (zebrafish embryogenesis) approaches both to improve our understanding of tissue-specific transcription factor function and to identify interpretable targets for non-coding mutations causing major eye malformations in the human genome.
1) Identify and categorise highly penetrant genomic mutations causing human eye malformations using family-based whole genome sequencing (WGS) and whole exome sequencing (WES) with particular focus on interpreting changes in the noncoding genome
2) Develop broadly applicable approaches to integrate the available clinical genomic data with quantitative (growth, developmental milestones) and categorical (HPO terms) phenotypic features to improve the diagnosis of known diseases and the discovery of new genes/genetic mechanisms.
3) Define the functional genomic characteristics of the transitions in gene regulatory networks (GRN) driving very early eye development using in vitro (human embryonic stem cells differentiation) and in vivo (zebrafish embryogenesis) approaches both to improve our understanding of tissue-specific transcription factor function and to identify interpretable targets for non-coding mutations causing major eye malformations in the human genome.
Organisations
People |
ORCID iD |
David FitzPatrick (Principal Investigator) |
Publications
Aitken S
(2019)
Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.
in American journal of human genetics
Ansari M
(2024)
Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features
in Human Genetics and Genomics Advances
Campbell J
(2018)
NALCN Dysfunction as a Cause of Disordered Respiratory Rhythm With Central Apnea.
in Pediatrics
Cif L
(2020)
KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.
in Brain : a journal of neurology
Connaughton DM
(2020)
Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.
in American journal of human genetics
FitzPatrick DR
(2020)
Genomically Aided Diagnosis of Severe Developmental Disorders.
in Annual review of genomics and human genetics
Hall HN
(2022)
Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia.
in PloS one
Hall HN
(2023)
Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia.
in Journal of medical genetics
Hall HN
(2019)
The genetic architecture of aniridia and Gillespie syndrome.
in Human genetics
Handley MT
(2019)
ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy.
in PLoS genetics
Hernandez-Moran BA
(2022)
Robust Genetic Analysis of the X-Linked Anophthalmic (Ie) Mouse.
in Genes
Johnston J
(2019)
NAA10 polyadenylation signal variants cause syndromic microphthalmia
in Journal of Medical Genetics
Kaplanis J
(2020)
Evidence for 28 genetic disorders discovered by combining healthcare and research data.
in Nature
Kline AD
(2018)
Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.
in Nature reviews. Genetics
Krab LC
(2020)
Delineation of phenotypes and genotypes related to cohesin structural protein RAD21.
in Human genetics
Lenassi E
(2023)
EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders.
in Journal of medical genetics
Lord J
(2019)
Pathogenicity and selective constraint on variation near splice sites.
in Genome research
Martin HC
(2021)
The contribution of X-linked coding variation to severe developmental disorders.
in Nature communications
Martin HC
(2018)
Quantifying the contribution of recessive coding variation to developmental disorders.
in Science (New York, N.Y.)
Männikkö R
(2018)
Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.
in Lancet (London, England)
Niemi MEK
(2018)
Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.
in Nature
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00007/1 | 31/03/2018 | 30/03/2023 | £662,000 | ||
MC_UU_00007/2 | Transfer | MC_UU_00007/1 | 31/03/2018 | 30/03/2023 | £3,730,000 |
MC_UU_00007/3 | Transfer | MC_UU_00007/2 | 31/03/2018 | 30/05/2022 | £3,053,000 |
MC_UU_00007/4 | Transfer | MC_UU_00007/3 | 31/03/2018 | 30/03/2023 | £1,772,000 |
MC_UU_00007/5 | Transfer | MC_UU_00007/4 | 31/03/2018 | 30/03/2023 | £4,524,000 |
MC_UU_00007/6 | Transfer | MC_UU_00007/5 | 31/03/2018 | 30/03/2023 | £2,878,000 |
MC_UU_00007/7 | Transfer | MC_UU_00007/6 | 31/03/2018 | 30/03/2023 | £2,829,000 |
MC_UU_00007/8 | Transfer | MC_UU_00007/7 | 31/03/2018 | 31/12/2022 | £4,072,000 |
MC_UU_00007/9 | Transfer | MC_UU_00007/8 | 31/03/2018 | 30/03/2023 | £3,137,000 |
MC_UU_00007/10 | Transfer | MC_UU_00007/9 | 31/03/2018 | 30/03/2023 | £6,948,000 |
MC_UU_00007/11 | Transfer | MC_UU_00007/10 | 31/03/2018 | 30/03/2023 | £2,421,000 |
MC_UU_00007/12 | Transfer | MC_UU_00007/11 | 31/03/2018 | 30/03/2023 | £1,205,000 |
MC_UU_00007/13 | Transfer | MC_UU_00007/12 | 31/03/2018 | 30/03/2023 | £1,174,000 |
MC_UU_00007/14 | Transfer | MC_UU_00007/13 | 31/03/2018 | 30/03/2023 | £1,838,000 |
MC_UU_00007/15 | Transfer | MC_UU_00007/14 | 31/03/2018 | 30/03/2023 | £2,551,000 |
MC_UU_00007/16 | Transfer | MC_UU_00007/15 | 31/03/2018 | 30/03/2023 | £1,496,000 |
MC_UU_00007/17 | Transfer | MC_UU_00007/16 | 31/03/2018 | 30/03/2023 | £1,886,000 |
Description | I gave three talks at the Fundamentals of Clinical Genomics and Variant Interpretation at Wellcome Conference Centre |
Geographic Reach | Europe |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | These were training talks delivered to clinical genetics and metabolic consultant and trainees on the use of diagnostic genomics and computational phenomics |
Description | Wellcome Trust Sanger Institute Foundations of Clinical Genetics Course |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Simons Initiative for the Developing Brain |
Amount | £20,000,000 (GBP) |
Organisation | Simons Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 05/2017 |
End | 06/2022 |
Title | CdLS |
Description | Collection of patients with Cornelia de Lange syndrome |
Type Of Material | Biological samples |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | WE have identified new mutations in NIPBL, SMC1A, HDAC8 and ANKRD11 |
Title | DDG2P Database |
Description | This is a genomic filtering tool to aid the diagnosis of developmental disorders using genome wide sequencing technologies such as whole exome and whole genome sequencing |
Type Of Material | Technology assay or reagent |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | This tool has been used to make diagnoses in thousands of children recruited to the DDD project |
URL | https://www.ebi.ac.uk/gene2phenotype/disclaimer |
Title | MEPA |
Description | MEPA cells are isolated from the mandibular or maxillary processes of embryonic mice carrying a temperature sensitive T-antigen. They express transcription factors that are critical to normal development of these structures |
Type Of Material | Cell line |
Year Produced | 2008 |
Provided To Others? | Yes |
Impact | These cells are crucial to the identification of mutations in specific regulatory sequences mutated in a subtype of cleft palate |
Title | DDG2P |
Description | This is a variant filtering tool which uses >2000 disease-gene pairs |
Type Of Material | Database/Collection of data |
Year Produced | 2012 |
Provided To Others? | Yes |
Impact | This database is an important component of the Deciphering Developmental Disorders project |
URL | http://www.ebi.ac.uk/gene2phenotype/disclaimer |
Description | DDD Project |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | I am one of the six coapplicants on the grant and I am a member of the management committee |
Collaborator Contribution | This project will allow is to perform high resolution genetic analysis and exome sequencing on 600 local cases with different developmental disorders. |
Impact | This project aims to analyse 12000 children in the UK with developmental disorders. |
Start Year | 2010 |
Description | Transforming Genetic Medicine Initiative (TGMI) |
Organisation | Addenbrooke's Hospital |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians |
Collaborator Contribution | There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills |
Impact | Improved clinical reporting of diagnostic genetic variants |
Start Year | 2016 |
Description | Transforming Genetic Medicine Initiative (TGMI) |
Organisation | EMBL European Bioinformatics Institute (EMBL - EBI) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians |
Collaborator Contribution | There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills |
Impact | Improved clinical reporting of diagnostic genetic variants |
Start Year | 2016 |
Description | Transforming Genetic Medicine Initiative (TGMI) |
Organisation | Institute of Cancer Research UK |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians |
Collaborator Contribution | There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills |
Impact | Improved clinical reporting of diagnostic genetic variants |
Start Year | 2016 |
Description | Transforming Genetic Medicine Initiative (TGMI) |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians |
Collaborator Contribution | There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills |
Impact | Improved clinical reporting of diagnostic genetic variants |
Start Year | 2016 |
Description | Transforming Genetic Medicine Initiative (TGMI) |
Organisation | University of Exeter |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians |
Collaborator Contribution | There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills |
Impact | Improved clinical reporting of diagnostic genetic variants |
Start Year | 2016 |
Description | McCance Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This is an invited named lecture to the Neonatology Society (UK). |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.bapm.org/events/the-neonatal-society-spring-meeting-2022 |
Description | Medical Director of the Cornelia de Lange Syndrome Foundation of UK and Ireland 2000-2016 |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I attend each of the 6-monthly national meetings of the CdLS foundation and meet with parents and children frequently to give results from our research diagnostic analysis We communicate research diagnostic results to individual families and their medical professionals |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017 |
URL | http://www.cdls.org.uk |
Description | Talk to the British Society for Genomic Medicine |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This was an invited talk to the BSGM which was to review the work we have been doing on the efficient path to a robust diagnosis using genome wide sequencing |
Year(s) Of Engagement Activity | 2019 |
Description | Talk to the Clinical Genetics Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This talk summarises what we have learned from the DDD project |
Year(s) Of Engagement Activity | 2019 |
URL | http://www.clingensoc.org/news-events/events/cgs-spring-meeting-2019/ |