Ciliopathy disease gene identification by whole exome medical resequencing
Lead Research Organisation:
University of Leeds
Department Name: School of Medicine
Abstract
Cilia are finger-like projections from cells that act as a cellular "antenna" to detect and respond to chemical or mechanical cues. One important cue is fluid flow during the process of establishing asymmetry during early embryogenesis, the formation of the kidney nephron, and the formation of other tubular structures such as the neural tube. A group of comparatively common inherited conditions called "ciliopathies" can arise when the structure or function of cilia are defective. For example, cystic kidney disease is a common feature of many ciliopathies, often leads to kidney failure, and is therefore a significant cause of childhood disease and death. The most severe ciliopathy ("Meckel-Gruber syndrome") also involves problems in the development of the brain and spinal cord (called "neural tube defects") that arise during growth of babies in the womb. Reduced or absent mucus clearance from the lungs is the main consequence in other ciliopathies ("primary ciliary dyskinesia"), which causes recurrent respiratory infections and progressive damage to the respiratory system. In many ciliopathies, there are disturbances in the patterns of left-right organization of the lungs and heart, which are also seen in congenital heart defects (CHD), the most common birth defect.
This research proposes to identify many of the remaining disease genes that are defective ("mutated") in this group of ciliopathies. To achieve this aim, we will take advantage of recent exciting advances in genetic technology that allow us to analyze the entire coding parts of a patient's genome ("whole exome sequencing"). We are uniquely placed to do this work and have a proven track record of success in this field: we have formed excellent research partnerships with families and their clinicians in the local community to participate in gene identification studies, and we have the appropriate state-of-the-art technology, computer analysis tools and experience.
The identification of a new ciliopathy gene provides two major benefits. Firstly, accurate genetic testing then becomes possible for patients and families, with improvements in diagnosis and genetic counselling. Secondly, important and often unexpected scientific insights are made into the disease mechanism of the ciliopathy and into the normal function of the disease gene, which can lead to new treatments. We also expect new insights into the causes of other, more common conditions such as polycystic kidney disease, spina bifida and congenital heart defects.
This research proposes to identify many of the remaining disease genes that are defective ("mutated") in this group of ciliopathies. To achieve this aim, we will take advantage of recent exciting advances in genetic technology that allow us to analyze the entire coding parts of a patient's genome ("whole exome sequencing"). We are uniquely placed to do this work and have a proven track record of success in this field: we have formed excellent research partnerships with families and their clinicians in the local community to participate in gene identification studies, and we have the appropriate state-of-the-art technology, computer analysis tools and experience.
The identification of a new ciliopathy gene provides two major benefits. Firstly, accurate genetic testing then becomes possible for patients and families, with improvements in diagnosis and genetic counselling. Secondly, important and often unexpected scientific insights are made into the disease mechanism of the ciliopathy and into the normal function of the disease gene, which can lead to new treatments. We also expect new insights into the causes of other, more common conditions such as polycystic kidney disease, spina bifida and congenital heart defects.
Technical Summary
We have ascertained and sampled DNA from about 250 individuals with a broad range of known or suspected ciliopathy phenotypes, but with a common theme of left-right laterality defects. These patients are confirmed to be mutation negative for known genes, or have been excluded from linkage to known loci in multiplex or consanguineous families. About 50% of disease genes for Meckel-Gruber syndrome and primary ciliary dyskinesia still remain to be identified, and many families with inherited forms of left-right laterality defects have an unknown genetic aetiology. We estimate that this research will identify a minimum of 10-12 new genes, comprising the majority of the remaining genes in this group of conditions. To discover new ciliopathy genes, we will perform whole exome sequencing for 100 individuals, including trios with an orphan ciliopathy. We will use our own successful bioinformatics workflow to distinguish putative pathogenic mutations from benign polymorphisms, even in the context of genetic heterogeneity. We will prioritize potential pathogenic variants in functional candidate genes on the basis of putative function, and our own data from a reverse genetics screen for ciliogenesis. Collaboration with other groups will allow us identify further mutations in a new gene for cohorts of patients with a ciliopathy and/or a retinal degeneration. This will also delineate an allelic series for a new gene, and may define genotype-phenotype correlations. We will collaborate with external groups to assess zebrafish embryo morphant phenotypes for 2 or 3 newly-identified ciliopathy disease genes. In some instances (for example if we need to prove the pathogenicity of a missense mutation), we will perform straight-forward functional characterization of the protein. This will include sub-cellular localization using confocal immunofluorescence microscopy and the effect of RNAi or a missense mutation on ciliogenesis or protein localization.
Planned Impact
Whole exome sequencing is very likely to improve the rate of molecular diagnosis in children with a known or suspected ciliopathy, and reduce the burden and disruption of a "diagnostic odyssey" for families. For clinicians, the identification of a new gene can also reduce misdiagnosis or late diagnosis, inform the establishment of proper care pathways for ciliopathy patients, and prioritize those patients that can most benefit from future targeted therapies. For example, patients with congenital heart disease (CHD) and heterotaxy have a high postsurgical morbidity and mortality, often developing respiratory complications, so prescreening for ciliary dysfunction or mutations in a ciliopathy gene may be of great potential benefit for CHD patients. CHD is the most common birth defect, affecting 1 in 150 live births or 3600 patients a year in the UK.
In families with a ciliopathy, the identification of a novel disease gene immediately permits the offer of genetic testing to at-risk relatives. Carrier tests and prenatal diagnosis can also encourage informed reproductive choices for families. In our experience, once a disease gene has been identified, genetic testing on a research basis can be applied immediately, and translation into service provision through an accredited NHS diagnostic lab can be made available in months. As a direct outcome of our own previous research, we have established UK-wide testing for Alström syndrome, Aicardi-Goutières syndrome and Meckel-Gruber syndrome (through the UK Genetic Testing Network and based at Yorkshire Regional Clinical Genetics Service). From our experiences of establishing NHS service testing using next-generation clonal sequencing at Yorkshire Regional Clinical Genetics Service, we fully expect that whole exome sequencing ("clinical exomes") will out-perform conventional diagnostic testing in terms of speed, sensitivity and cost. There are therefore considerable potential cost savings for NHS Trusts, but the fundamental challenge in analyzing exome sequence data is then distinguishing pathogenic mutations from benign polymorphisms, particularly in the context of genetically heterogeneous conditions such as the ciliopathies. Our ability to overcome this challenge will inform the debate on the eventual clinical utility and clinical validity of "clinical exomes", and the probable widespread adoption of whole exome sequencing as a routine diagnostic strategy. In particular, we are keen to retain key researchers with key bioinformatic skills so that their knowledge can stimulate the adoption of clinical bioinformatics expertise, and the use of standardized databases of normal and pathogenic genomic variation. The development of a robust interface between research and diagnostic development work is therefore an indirect but important added benefit of this research, which should encourage the implementation of NGS for the diagnosis of genetic diseases in other clinical centres.
The identification of further novel ciliopathy disease genes may also enable the future rational design of therapeutics to modify or treat cystic kidney disease or ciliopathy disease progression, or the long-term outlook of patients with these conditions. Since most of these conditions are autosomal recessive and are the result of absence of normal protein, rather than the presence of an abnormal protein, they can in principle be corrected by gene-replacement, a therapeutic approach now undergoing Phase II clinical trials in major centres in the US, UK and elsewhere. Patients in whom mutations are found can therefore be given a clearer prognosis and prioritised for these new treatments, making recessive disease a top priority for further characterization.
In families with a ciliopathy, the identification of a novel disease gene immediately permits the offer of genetic testing to at-risk relatives. Carrier tests and prenatal diagnosis can also encourage informed reproductive choices for families. In our experience, once a disease gene has been identified, genetic testing on a research basis can be applied immediately, and translation into service provision through an accredited NHS diagnostic lab can be made available in months. As a direct outcome of our own previous research, we have established UK-wide testing for Alström syndrome, Aicardi-Goutières syndrome and Meckel-Gruber syndrome (through the UK Genetic Testing Network and based at Yorkshire Regional Clinical Genetics Service). From our experiences of establishing NHS service testing using next-generation clonal sequencing at Yorkshire Regional Clinical Genetics Service, we fully expect that whole exome sequencing ("clinical exomes") will out-perform conventional diagnostic testing in terms of speed, sensitivity and cost. There are therefore considerable potential cost savings for NHS Trusts, but the fundamental challenge in analyzing exome sequence data is then distinguishing pathogenic mutations from benign polymorphisms, particularly in the context of genetically heterogeneous conditions such as the ciliopathies. Our ability to overcome this challenge will inform the debate on the eventual clinical utility and clinical validity of "clinical exomes", and the probable widespread adoption of whole exome sequencing as a routine diagnostic strategy. In particular, we are keen to retain key researchers with key bioinformatic skills so that their knowledge can stimulate the adoption of clinical bioinformatics expertise, and the use of standardized databases of normal and pathogenic genomic variation. The development of a robust interface between research and diagnostic development work is therefore an indirect but important added benefit of this research, which should encourage the implementation of NGS for the diagnosis of genetic diseases in other clinical centres.
The identification of further novel ciliopathy disease genes may also enable the future rational design of therapeutics to modify or treat cystic kidney disease or ciliopathy disease progression, or the long-term outlook of patients with these conditions. Since most of these conditions are autosomal recessive and are the result of absence of normal protein, rather than the presence of an abnormal protein, they can in principle be corrected by gene-replacement, a therapeutic approach now undergoing Phase II clinical trials in major centres in the US, UK and elsewhere. Patients in whom mutations are found can therefore be given a clearer prognosis and prioritised for these new treatments, making recessive disease a top priority for further characterization.
Organisations
- University of Leeds (Lead Research Organisation)
- LEEDS TEACHING HOSPITALS NHS TRUST (Collaboration)
- University of Sheffield (Collaboration)
- Duke University (Collaboration)
- Birmingham Women's Hospital (Collaboration)
- Newcastle University (Collaboration)
- Sheffield Children's NHS Foundation Trust (Collaboration)
- University Medical Center Utrecht (UMC) (Collaboration)
Publications
Shaheen R
(2014)
Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans.
in American journal of human genetics
Mirzaa G
(2014)
De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.
in Nature genetics
Logan CV
(2014)
Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling.
in Nature genetics
Szymanska K
(2014)
Unraveling the genetics of Joubert and Meckel-Gruber syndromes.
in Journal of pediatric genetics
Mans DA
(2014)
Medical genetics of ciliopathies.
in Journal of pediatric genetics
Wheway G
(2014)
The role of primary cilia in the development and disease of the retina.
in Organogenesis
Title | Additional file 1: Figure S1. of Characterizing the morbid genome of ciliopathies |
Description | Bar graph showing the percentage of the main features for each distinct ciliopathy syndrome. (PPTX 70 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2016 |
URL | https://springernature.figshare.com/articles/presentation/Additional_file_1_Figure_S1_of_Characteriz... |
Title | Additional file 1: Figure S1. of Characterizing the morbid genome of ciliopathies |
Description | Bar graph showing the percentage of the main features for each distinct ciliopathy syndrome. (PPTX 70 kb) |
Type Of Art | Film/Video/Animation |
Year Produced | 2016 |
URL | https://springernature.figshare.com/articles/presentation/Additional_file_1_Figure_S1_of_Characteriz... |
Description | 100K Genome Project: outreach |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | diagnosis and treatment of neurodevelopmental conditions |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Our research has enabled a new recognition of the broad range of phenotype for neurodevelopmental conditions such as Joubert syndrome. The identification of new genes provided more accurate prognostic testing and genetic counselling, with national NHS service testing for both Meckel-Gruber and Joubert syndromes now based at Yorkshire Regional Genetics Service. New services based on clinical whole exome sequencing has enabled testing of about 40-60 patients per annum for both the UK and for international referrals. |
Description | recessive conditions |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | greater investment in clinical genetics and training of genetic counsellors, greater awareness of recessive conditions and rare diseases |
Description | Bilateral BBSRC-SFI (structure-function relationships in the ciliary transition zone) |
Amount | £576,400 (GBP) |
Funding ID | BB/P007791/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2021 |
Description | Elucidating splicing factor function and retinal splicing programmes: developing new therapeutic strategies for splicing factor retinitis pigmentosa |
Amount | £1,456,000 (GBP) |
Funding ID | MR/T017503/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2020 |
End | 12/2024 |
Description | MRC project grant (functional genomics) |
Amount | £856,000 (GBP) |
Funding ID | MR/M000532/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2014 |
End | 09/2017 |
Description | PhD Training Fellowship for Clinicians "Developing variant interpretation pipelines for inherited retinal diseases and ciliopathies: using medical genomics to improve diagnostic yield" |
Amount | £250,000 (GBP) |
Funding ID | UNS81212 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 09/2021 |
Description | Pre-clinical testing of ROCK2 inhibition as a new therapeutic treatment for cystic kidney diseases |
Amount | £249,459 (GBP) |
Funding ID | PKD_RP_006_20211124 |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2022 |
End | 05/2025 |
Description | Pre-clinical testing of new therapeutic treatments for cystic kidney disease |
Amount | £200,000 (GBP) |
Funding ID | GN2628 |
Organisation | University of Leeds |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2018 |
End | 06/2021 |
Title | MKS patient cohort |
Description | cohort of ciliopathy patients, sampled for DNA with assessment of mutation status and clinical phenotype |
Type Of Material | Biological samples |
Year Produced | 2007 |
Provided To Others? | Yes |
Impact | role of RPGRIP1L in determining a retinal phenotype in ciliopathies; mutation screening in other ciliopathy genes eg ARL13B, TMEM216, TMEM138. TMEM237 etc |
Title | WES variant analysis and filtering |
Description | developed standard workflow for analysis of variants from WES experiments based on existing publically-available databases (EVS, 1000 Genomes etc) and in-house ethnically-matched exomes bespoke Perl scripts developed to allow automated annotation of candidate genes, pathogenic potential of variants (from Condel, Polyphen etc), segregation analysis in small families with recessive or dominant inheritance patterns |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | Parry DA,et al. (2013). SAMS, a syndrome of short stature, auditory canal atresia, mandibular hypoplasia and skeletal abnormalities is a unique neurocristopathy caused by mutations in Goosecoid. Am. J. Hum. Genet. in press Khan K, et al. (2012). Next generation sequencing identifies mutations in Atonal homolog 7 (ATOH7) in families with global eye developmental defects. Hum Mol Genet. 21: 776-83. Logan CV, et al. (2011). Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Nat. Genet. 43: 1189-1192 |
URL | http://autozygosity.org |
Title | genetic & small molecule effectors of ciliogenesis |
Description | 1) list of validated candidate genes implicated in ciliogenesis, cilia maintenance and cilia length growth as a result of a whole genome cell-based reverse genetics visual screen primary list: ca. 600 genes secondary screen list: 174 genes tertiary validated genes: ca. 42 genes selected functional candidates: 14 genes 2) RNA-Seq expression data and exon usage from non-ciliated vs. ciliated cell-lines, wild-type and mutant dermal fibroblasts, iPSCs, and iPSC-derived cell types (retinal pigment epithelium, retinal organoids, kidney organoids) 3) |
Type Of Material | Technology assay or reagent |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | methodlogies of assessing cell numbers, cellular & ciliary phenotypes in a series of visual screens are described in this publications: Elmehdawi F, et al. (2013) Human Homologue of Drosophila Ariadne (HHARI) is a marker of cellular proliferation associated with nuclear bodies. Exp. Cell Res. 319:161-172. Wheway G, et al. (2015). An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat. Cell. Biol. 17: 1074-87 Buskin A, et al. (2018). Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun 9:4234 Lake AL et al. (2020) Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies; https://www.biorxiv.org/content/10.1101/2020.11.26.393801v1 |
URL | http://www.syscilia.org |
Title | Additional file 2: Table S3. of Characterizing the morbid genome of ciliopathies |
Description | Clinical and genomic data for all cases in the study. (XLSX 83 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_2_Table_S3_of_Characterizing_th... |
Title | Additional file 2: Table S3. of Characterizing the morbid genome of ciliopathies |
Description | Clinical and genomic data for all cases in the study. (XLSX 83 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_2_Table_S3_of_Characterizing_th... |
Title | Additional file 5: Table S4. of Characterizing the morbid genome of ciliopathies |
Description | Identification of TXNDC15 interacting proteins using tandem affinity purification (TAP). The list of 224 unique proteins is significantly enriched in known or predicted ciliary proteins. (XLSX 30 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_5_Table_S4_of_Characterizing_th... |
Title | Additional file 5: Table S4. of Characterizing the morbid genome of ciliopathies |
Description | Identification of TXNDC15 interacting proteins using tandem affinity purification (TAP). The list of 224 unique proteins is significantly enriched in known or predicted ciliary proteins. (XLSX 30 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_5_Table_S4_of_Characterizing_th... |
Title | Additional file 6: Table S5. of Characterizing the morbid genome of ciliopathies |
Description | Ciliopathy disease burden in the population for each pathogenic variant identified in known ciliopathy genes. (XLSX 19 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_6_Table_S5_of_Characterizing_th... |
Title | Additional file 6: Table S5. of Characterizing the morbid genome of ciliopathies |
Description | Ciliopathy disease burden in the population for each pathogenic variant identified in known ciliopathy genes. (XLSX 19 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_6_Table_S5_of_Characterizing_th... |
Title | Additional file 7: Table S6. of Characterizing the morbid genome of ciliopathies |
Description | List of common variants with MAF of >0.01 that are listed as â disease-causingâ variants in HGMD for known ciliopathy genes. (XLSX 12 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_7_Table_S6_of_Characterizing_th... |
Title | Additional file 7: Table S6. of Characterizing the morbid genome of ciliopathies |
Description | List of common variants with MAF of >0.01 that are listed as â disease-causingâ variants in HGMD for known ciliopathy genes. (XLSX 12 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_7_Table_S6_of_Characterizing_th... |
Title | Additional file 8: Table S1. of Characterizing the morbid genome of ciliopathies |
Description | List of diagnostic criteria used to clinically classify each ciliopathy. (XLSX 10 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_8_Table_S1_of_Characterizing_th... |
Title | Additional file 8: Table S1. of Characterizing the morbid genome of ciliopathies |
Description | List of diagnostic criteria used to clinically classify each ciliopathy. (XLSX 10 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_8_Table_S1_of_Characterizing_th... |
Title | effectors of ciliogenesis |
Description | list of validated candidate genes implicated in ciliogenesis, cilia maintenance and cilia length growth as a result of a whole genome cell-based reverse genetics visual screen primary list: ca. 600 genes secondary screen list: 174 genes tertiary validated genes: ca. 42 genes selected functional candidates: 14 genes other date includes RNA-Seq expression data from non-ciliated vs. ciliated cell-lines |
Type Of Material | Database/Collection of data |
Provided To Others? | No |
Impact | Wheway G*, Schmidts M*, Mans DA*, Szymanska K*, Nguyen T-MT*, ...69 others... Doherty D+, Mitchison HM+, Roepman R+, Johnson CA+ (2015). An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat. Cell. Biol. 17: 1074-87 |
Description | medical resequencing of ciliopathy genes |
Organisation | Birmingham Women's Hospital |
Department | Clinical Genetics |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants |
Collaborator Contribution | access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients |
Impact | the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009 |
Start Year | 2006 |
Description | medical resequencing of ciliopathy genes |
Organisation | Duke University |
Department | Department of Cell Biology |
Country | United States |
Sector | Academic/University |
PI Contribution | ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants |
Collaborator Contribution | access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients |
Impact | the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009 |
Start Year | 2006 |
Description | medical resequencing of ciliopathy genes |
Organisation | Leeds Teaching Hospitals NHS Trust |
Department | Yorkshire Regional Genetics Service & Clinical Genetics |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants |
Collaborator Contribution | access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients |
Impact | the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009 |
Start Year | 2006 |
Description | medical resequencing of ciliopathy genes |
Organisation | Newcastle University |
Department | Institute of Genetic Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants |
Collaborator Contribution | access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients |
Impact | the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009 |
Start Year | 2006 |
Description | medical resequencing of ciliopathy genes |
Organisation | Sheffield Children's NHS Foundation Trust |
Department | Clinical Genetics |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | ascertained fmailies affected with ciliopathies, screened known genes, collated clinical data, verified mutations, exluded polymorphic variants |
Collaborator Contribution | access the high-throughput resequencing technology and techniques for assessing the pathogenic potential of missense variants; whole exome sequendcing of ciliopathy patients |
Impact | the A229T change in the RPGRIP1L gene is associated with retinal features in ciliopathies; published in Nat. Genet. 2009 |
Start Year | 2006 |
Description | zebrafish models of human disease |
Organisation | Newcastle University |
Department | Institute of Genetic Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | candidates genes with putative pathogenic mutations for recessive developmental or cardiac conditions are modelled in wild-type zebrafish embryos using morpholino knockdown, or novel mutations are knocked-in using the CRISPR-Cas9 system |
Collaborator Contribution | access to zebrafish husbandry and microinjection facilities; assessment of embryo phenotypes |
Impact | two manuscripts in the drafting stage, reporting novel genes mutated in a retinal dystrophy and Meckel-Gruber syndrome (a severe ciliopathy), and a form of primary ciliary dyskinesia that manifests only with cardiac heterotaxy |
Start Year | 2013 |
Description | zebrafish models of human disease |
Organisation | University Medical Center Utrecht (UMC) |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | candidates genes with putative pathogenic mutations for recessive developmental or cardiac conditions are modelled in wild-type zebrafish embryos using morpholino knockdown, or novel mutations are knocked-in using the CRISPR-Cas9 system |
Collaborator Contribution | access to zebrafish husbandry and microinjection facilities; assessment of embryo phenotypes |
Impact | two manuscripts in the drafting stage, reporting novel genes mutated in a retinal dystrophy and Meckel-Gruber syndrome (a severe ciliopathy), and a form of primary ciliary dyskinesia that manifests only with cardiac heterotaxy |
Start Year | 2013 |
Description | zebrafish models of human disease |
Organisation | University of Sheffield |
Department | MRC Centre for Developmental and Biomedical Genetics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | candidates genes with putative pathogenic mutations for recessive developmental or cardiac conditions are modelled in wild-type zebrafish embryos using morpholino knockdown, or novel mutations are knocked-in using the CRISPR-Cas9 system |
Collaborator Contribution | access to zebrafish husbandry and microinjection facilities; assessment of embryo phenotypes |
Impact | two manuscripts in the drafting stage, reporting novel genes mutated in a retinal dystrophy and Meckel-Gruber syndrome (a severe ciliopathy), and a form of primary ciliary dyskinesia that manifests only with cardiac heterotaxy |
Start Year | 2013 |
Title | NHS service testing for ciliopathies |
Description | First use of clinical whole exome sequencing by the Yorkshire Regional Genetics Service for the diagnosis of ciliopathies (primary ciliary dyskinesia, Meckel-Gruber syndrome, Joubert syndrome). New services based on clinical whole exome sequencing has enabled testing of about 40-60 patients per annum for both the UK and for international referrals. |
Type | Diagnostic Tool - Non-Imaging |
Current Stage Of Development | Wide-scale adoption |
Year Development Stage Completed | 2013 |
Development Status | Under active development/distribution |
Impact | Improved diagnosis, prognosis and genetic counselling for ciliopathy patients and their families |
URL | http://www.leedsth.nhs.uk/a-z-of-services/molecular-genetics/test-pages/meckel-and-joubert-syndromes... |
Description | BioJapan2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | presented current methodologies used for functional interpretation of mutations in rare Mendelian conditions using CRISPR-Cas9 genome and base editing; the presentation was to a large mixed audience of industry, big pharma and basic reseachers followed by a debate on ethic issues |
Year(s) Of Engagement Activity | 2017 |
Description | Cafe Scientifique |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | About 50 attendees to the Cafe Scientifique meeting in Feb 2020; I presented on recent advances in the diagnosis and treatment of inherited blindness, and was able to answer questions and speak to patients and supporters after the formal presentation. |
Year(s) Of Engagement Activity | 2020 |
Description | Cilia in Development and Disease |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | contributed to organization and programme for these international conferences new research collaborations were started as a result of these conferences |
Year(s) Of Engagement Activity | 2012,2014 |
Description | Ciliopathy Alliance UK |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | promoted support group attendance at the international conference "Cilia 2012" in London 2012 continuing links with support groups (Joubert Syndrome UK and Alstrom Syndrome UK) |
Year(s) Of Engagement Activity | 2009,2010,2011,2012 |
Description | FASEB "Polycystic Kidney Disease" meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | to facillitate and establish research collabirations, with critique of current research |
Year(s) Of Engagement Activity | 2017 |
Description | ISN Forefronts Symposium on PKD |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | keynote/invited speaker |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | a general overview of my group's work on Meckel-Gruber syndrome and other ciliopathies, to an audience of researchers and clincians working on Polycystic Kidney Disease the meeting was very useful as an informal venue to establish new collaborations with some existing collaborators |
Year(s) Of Engagement Activity | 2008 |
Description | Johnson Lab Twitter feed |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Twitter feed for the lab group which reports on our professional activities and events |
Year(s) Of Engagement Activity | 2020 |
URL | https://twitter.com/johnsoncilialab |
Description | Joubert syndrome scientific meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | keynote/invited speaker |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | imporant discussion on the improved methods for diagnosis of Joubert syndrome and other ciliopathies, as well as new insights into pathogenic mechanisms promoting new collaborations with workers in the field of Joubert syndrome |
Year(s) Of Engagement Activity | 2013 |
Description | Midbrain/Hindbrain Malformations and Hydrocephalus workshop |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Type Of Presentation | keynote/invited speaker |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | important opportunity to compare methods of diagnosis for ciliopathies and provided new insights into development of the cerebullum and posterior fossa structures initiated new collaborations as part of on-going discussions |
Year(s) Of Engagement Activity | 2014 |
Description | PEGS Boston 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | presented current methodologies used for functional interpretation of mutations in rare Mendelian conditions using CRISPR-Cas9 genome and base editing; the presentation was to a large mixed audience of industry, big pharma and basic reseachers followed by a debate on ethic issues |
Year(s) Of Engagement Activity | 2018 |
Description | UK Cilia Club |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | informal research club for reseachers in the north of England and Scotland; first meeting was in Sheffield Sept 2014, with on-going meetings planned for every 6 months in Leeds, Newcastle adn Edinburgh new collaboration with University of Newcastle |
Year(s) Of Engagement Activity | 2014,2015,2016,2017,2018 |
Description | autozygosity.org website |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | a website inititated and maintained by Prof. David Bonthron at the University of Leeds to summarize our work on autozygosity mapping of recessive inherited conditions increased clinical collaboration and publicity |
Year(s) Of Engagement Activity | 2008,2009,2010,2011,2012,2013,2014 |
URL | http://www.autozygosity.org |
Description | genetics and cell biology of Meckel-Gruber syndrome |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Health professionals |
Results and Impact | a overview of the molecular genetics and cell biology of ciliopathies, focussing on Meckel-Gruber syndrome, to an audience of medical and clinical geneticists useful to establish clinical collaborations on other ciliopathies (notably family ascertainment for Ivemark syndrome) |
Year(s) Of Engagement Activity | 2008,2009,2010,2011,2012,2013,2014 |
Description | school out-reach activities |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | discussed careers in medical research with about 60 Year 12 and 13 students on a visit and presentation at their school; 10 had a follow-on visit to the lab to discuss research methods |
Year(s) Of Engagement Activity | 2015,2016,2017,2018 |