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  1. Article ; Online: Reduced penetrance of gene variants causing amyotrophic lateral sclerosis.

    Douglas, Andrew G L / Baralle, Diana

    Journal of medical genetics

    2024  Volume 61, Issue 3, Page(s) 294–297

    Abstract: Background: Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are : Objective: We sought to determine the ... ...

    Abstract Background: Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are
    Objective: We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis.
    Methods: Published epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data for
    Results: Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for
    Conclusion: Population-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/epidemiology ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; Frontotemporal Dementia/epidemiology ; Frontotemporal Dementia/genetics ; C9orf72 Protein/genetics ; Penetrance ; Superoxide Dismutase-1/genetics
    Chemical Substances C9orf72 Protein ; Superoxide Dismutase-1 (EC 1.15.1.1)
    Language English
    Publishing date 2024-02-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmg-2023-109580
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  2. Article ; Online: Epidemiology of Robin sequence: geographical variation in the UK/Ireland.

    Atton, Giles / Baralle, Diana

    Archives of disease in childhood

    2024  Volume 109, Issue 3, Page(s) 177–178

    MeSH term(s) Humans ; Ireland/epidemiology ; Pierre Robin Syndrome ; United Kingdom/epidemiology
    Language English
    Publishing date 2024-02-19
    Publishing country England
    Document type Editorial
    ZDB-ID 524-1
    ISSN 1468-2044 ; 0003-9888 ; 1359-2998
    ISSN (online) 1468-2044
    ISSN 0003-9888 ; 1359-2998
    DOI 10.1136/archdischild-2023-326079
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  3. Article: Splicing in the Diagnosis of Rare Disease: Advances and Challenges.

    Lord, Jenny / Baralle, Diana

    Frontiers in genetics

    2021  Volume 12, Page(s) 689892

    Abstract: Mutations which affect splicing are significant contributors to rare disease, but are frequently overlooked by diagnostic sequencing pipelines. Greater ascertainment of pathogenic splicing variants will increase diagnostic yields, ending the diagnostic ... ...

    Abstract Mutations which affect splicing are significant contributors to rare disease, but are frequently overlooked by diagnostic sequencing pipelines. Greater ascertainment of pathogenic splicing variants will increase diagnostic yields, ending the diagnostic odyssey for patients and families affected by rare disorders, and improving treatment and care strategies. Advances in sequencing technologies, predictive modeling, and understanding of the mechanisms of splicing in recent years pave the way for improved detection and interpretation of splice affecting variants, yet several limitations still prohibit their routine ascertainment in diagnostic testing. This review explores some of these advances in the context of clinical application and discusses challenges to be overcome before these variants are comprehensively and routinely recognized in diagnostics.
    Language English
    Publishing date 2021-07-01
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606823-0
    ISSN 1664-8021
    ISSN 1664-8021
    DOI 10.3389/fgene.2021.689892
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  4. Article ; Online: CI-SpliceAI-Improving machine learning predictions of disease causing splicing variants using curated alternative splice sites.

    Strauch, Yaron / Lord, Jenny / Niranjan, Mahesan / Baralle, Diana

    PloS one

    2022  Volume 17, Issue 6, Page(s) e0269159

    Abstract: Background: It is estimated that up to 50% of all disease causing variants disrupt splicing. Due to its complexity, our ability to predict which variants disrupt splicing is limited, meaning missed diagnoses for patients. The emergence of machine ... ...

    Abstract Background: It is estimated that up to 50% of all disease causing variants disrupt splicing. Due to its complexity, our ability to predict which variants disrupt splicing is limited, meaning missed diagnoses for patients. The emergence of machine learning for targeted medicine holds great potential to improve prediction of splice disrupting variants. The recently published SpliceAI algorithm utilises deep neural networks and has been reported to have a greater accuracy than other commonly used methods.
    Methods and findings: The original SpliceAI was trained on splice sites included in primary isoforms combined with novel junctions observed in GTEx data, which might introduce noise and de-correlate the machine learning input with its output. Limiting the data to only validated and manual annotated primary and alternatively spliced GENCODE sites in training may improve predictive abilities. All of these gene isoforms were collapsed (aggregated into one pseudo-isoform) and the SpliceAI architecture was retrained (CI-SpliceAI). Predictive performance on a newly curated dataset of 1,316 functionally validated variants from the literature was compared with the original SpliceAI, alongside MMSplice, MaxEntScan, and SQUIRLS. Both SpliceAI algorithms outperformed the other methods, with the original SpliceAI achieving an accuracy of ∼91%, and CI-SpliceAI showing an improvement at ∼92% overall. Predictive accuracy increased in the majority of curated variants.
    Conclusions: We show that including only manually annotated alternatively spliced sites in training data improves prediction of clinically relevant variants, and highlight avenues for further performance improvements.
    MeSH term(s) Alternative Splicing ; Humans ; Machine Learning ; Mutation ; Neural Networks, Computer ; RNA Splice Sites/genetics ; RNA Splicing
    Chemical Substances RNA Splice Sites
    Language English
    Publishing date 2022-06-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0269159
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  5. Article ; Online: 'Next Generation Sequencing' as a diagnostic tool in paediatrics.

    Baralle, Diana / Ismail, Vardha

    Archives of disease in childhood

    2020  Volume 106, Issue 1, Page(s) 1–2

    MeSH term(s) Child ; High-Throughput Nucleotide Sequencing ; Humans ; Pediatrics
    Language English
    Publishing date 2020-10-29
    Publishing country England
    Document type Editorial ; Comment
    ZDB-ID 524-1
    ISSN 1468-2044 ; 0003-9888 ; 1359-2998
    ISSN (online) 1468-2044
    ISSN 0003-9888 ; 1359-2998
    DOI 10.1136/archdischild-2020-320251
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  6. Article ; Online: Essentiality-specific pathogenicity prioritization gene score to improve filtering of disease sequence data.

    Alyousfi, Dareen / Baralle, Diana / Collins, Andrew

    Briefings in bioinformatics

    2020  Volume 22, Issue 2, Page(s) 1782–1789

    Abstract: The causal genetic variants underlying more than 50% of single gene (monogenic) disorders are yet to be discovered. Many patients with conditions likely to have a monogenic basis do not receive a confirmed molecular diagnosis which has potential impacts ... ...

    Abstract The causal genetic variants underlying more than 50% of single gene (monogenic) disorders are yet to be discovered. Many patients with conditions likely to have a monogenic basis do not receive a confirmed molecular diagnosis which has potential impacts on clinical management. We have developed a gene-specific score, essentiality-specific pathogenicity prioritization (ESPP), to guide the recognition of genes likely to underlie monogenic disease variation to assist in filtering of genome sequence data. When a patient genome is sequenced, there are frequently several plausibly pathogenic variants identified in different genes. Recognition of the single gene most likely to include pathogenic variation can guide the identification of a causal variant. The ESPP score integrates gene-level scores which are broadly related to gene essentiality. Previous work towards the recognition of monogenic disease genes proposed a model with increasing gene essentiality from 'non-essential' to 'essential' genes (for which pathogenic variation may be incompatible with survival) with genes liable to contain disease variation positioned between these two extremes. We demonstrate that the ESPP score is useful for recognizing genes with high potential for pathogenic disease-related variation. Genes classed as essential have particularly high scores, as do genes recently recognized as strong candidates for developmental disorders. Through the integration of individual gene-specific scores, which have different properties and assumptions, we demonstrate the utility of an essentiality-based gene score to improve sequence genome filtering.
    MeSH term(s) Genes, Essential ; Humans ; Virulence/genetics ; Whole Genome Sequencing/methods
    Language English
    Publishing date 2020-02-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2068142-2
    ISSN 1477-4054 ; 1467-5463
    ISSN (online) 1477-4054
    ISSN 1467-5463
    DOI 10.1093/bib/bbaa029
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  7. Article ; Online: Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy.

    Wheway, Gabrielle / Douglas, Andrew / Baralle, Diana / Guillot, Elsa

    Experimental eye research

    2020  Volume 192, Page(s) 107950

    Abstract: Pathogenic variants in pre-messenger RNA (pre-mRNA) splicing factor 31, PRPF31, are the second most common genetic cause of autosomal dominant retinitis pigmentosa (adRP) in most populations. This remains a completely untreatable and incurable form of ... ...

    Abstract Pathogenic variants in pre-messenger RNA (pre-mRNA) splicing factor 31, PRPF31, are the second most common genetic cause of autosomal dominant retinitis pigmentosa (adRP) in most populations. This remains a completely untreatable and incurable form of blindness, and it can be difficult to predict the clinical course of disease. In order to design appropriate targeted therapies, a thorough understanding of the genetics and molecular mechanism of this disease is required. Here, we present the structure of the PRPF31 gene and PRPF31 protein, current understanding of PRPF31 protein function and the full spectrum of all reported clinically relevant variants in PRPF31. We delineate the correlation between specific PRPF31 genotype and RP phenotype, suggesting that, except in cases of complete gene deletion or large-scale deletions, dominant negative effects contribute to phenotype as well as haploinsufficiency. This has important impacts on design of targeted therapies, particularly the feasibility of gene augmentation as a broad approach for treatment of PRPF31-associated RP. We discuss other opportunities for therapy, including antisense oligonucleotide therapy and gene-independent approaches and offer future perspectives on treatment of this form of RP.
    MeSH term(s) DNA Mutational Analysis ; Electroretinography ; Eye Proteins/genetics ; Female ; Genetic Association Studies ; Genetic Therapy ; Humans ; Male ; Mutation/genetics ; Oligonucleotides, Antisense ; Polymerase Chain Reaction ; RNA Splicing ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/therapy
    Chemical Substances Eye Proteins ; Oligonucleotides, Antisense ; PRPF31 protein, human
    Language English
    Publishing date 2020-01-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80122-7
    ISSN 1096-0007 ; 0014-4835
    ISSN (online) 1096-0007
    ISSN 0014-4835
    DOI 10.1016/j.exer.2020.107950
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  8. Article ; Online: A severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome with a novel description of coloboma and septo-optic dysplasia, owing to a start codon variant in the NR2F1 gene.

    Gazdagh, Gabriella / Mawby, Rebecca / Self, Jay E / Baralle, Diana

    American journal of medical genetics. Part A

    2021  Volume 188, Issue 3, Page(s) 900–906

    Abstract: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare congenital syndrome characterized by a range of phenotypes including optic atrophy and intellectual disability among other features. Pathogenic variants in the NR2F1 (nuclear receptor ... ...

    Abstract Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare congenital syndrome characterized by a range of phenotypes including optic atrophy and intellectual disability among other features. Pathogenic variants in the NR2F1 (nuclear receptor subfamily 2 group F member 1) gene have been linked to this condition. A recent report has shown that pathogenic variants in the start codon lead to decreased expression of the NR2F1 protein and a relatively mild phenotype, similar to that seen in whole gene deletions, and due to the lack of the dominant negative effect. Here we describe a severe case of BBSOAS with an initiation codon missense variant. The developmental delay, seizures, optic atrophy are in keeping with features observed in this condition, however this is the first report to describe colobomas and septo-optic dysplasia as associated features potentially extending the phenotype linked to BBSOAS. In addition, this is the first description of a severe phenotype linked to a de novo missense variant in the start codon of the NR2F1 gene.
    MeSH term(s) COUP Transcription Factor I/genetics ; Codon, Initiator ; Coloboma/genetics ; Humans ; Intellectual Disability/genetics ; Optic Atrophies, Hereditary/genetics ; Optic Atrophy/diagnosis ; Optic Atrophy/genetics ; Septo-Optic Dysplasia/diagnosis ; Septo-Optic Dysplasia/genetics
    Chemical Substances COUP Transcription Factor I ; Codon, Initiator ; NR2F1 protein, human
    Language English
    Publishing date 2021-11-17
    Publishing country United States
    Document type Case Reports ; Research Support, Non-U.S. Gov't
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.62569
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  9. Article ; Online: Response to Ramos et al.

    Seaby, Eleanor G / Baralle, Diana / Rehm, Heidi L / O'Donnell-Luria, Anne / Ennis, Sarah

    Genetics in medicine : official journal of the American College of Medical Genetics

    2022  Volume 24, Issue 12, Page(s) 2593–2594

    Language English
    Publishing date 2022-09-19
    Publishing country United States
    Document type Letter
    ZDB-ID 1455352-1
    ISSN 1530-0366 ; 1098-3600
    ISSN (online) 1530-0366
    ISSN 1098-3600
    DOI 10.1016/j.gim.2022.08.016
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  10. Article: A Panel-Agnostic Strategy 'HiPPo' Improves Diagnostic Efficiency in the UK Genomic Medicine Service.

    Seaby, Eleanor G / Thomas, N Simon / Hunt, David / Baralle, Diana / Rehm, Heidi L / O'Donnell-Luria, Anne / Ennis, Sarah

    Healthcare (Basel, Switzerland)

    2023  Volume 11, Issue 24

    Abstract: Genome sequencing is available as a clinical test in the UK through the Genomic Medicine Service (GMS). The GMS analytical strategy predominantly filters genome data on preselected gene panels. Whilst this reduces variants requiring assessment by ... ...

    Abstract Genome sequencing is available as a clinical test in the UK through the Genomic Medicine Service (GMS). The GMS analytical strategy predominantly filters genome data on preselected gene panels. Whilst this reduces variants requiring assessment by reporting laboratories, pathogenic variants outside applied panels may be missed, and variants in genes without established disease-gene relationships are largely ignored. This study compares the analysis of a research exome to a GMS clinical genome for the same patients. For the research exome, we applied a panel-agnostic approach filtering for variants with
    Language English
    Publishing date 2023-12-15
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2721009-1
    ISSN 2227-9032
    ISSN 2227-9032
    DOI 10.3390/healthcare11243179
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