Publications by authors named "G Jane Farrar"

311 Publications

Molecular Inversion Probe-Based Sequencing of Exons and Splice Sites as a Cost-Effective Screening Tool in USH2 and arRP Cases.

Int J Mol Sci 2021 Jun 15;22(12). Epub 2021 Jun 15.

Department of Human Genetics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 Nijmegen, The Netherlands.

A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic variants. Molecular inversion probe (MIP)-based sequencing was performed for the exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for . Seven unexplained cases were selected for future analysis with whole genome sequencing.
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http://dx.doi.org/10.3390/ijms22126419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232728PMC
June 2021

Next-Generation Sequencing Applications for Inherited Retinal Diseases.

Int J Mol Sci 2021 May 26;22(11). Epub 2021 May 26.

The School of Genetics & Microbiology, Trinity College Dublin, Dublin 2, Ireland.

Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.
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http://dx.doi.org/10.3390/ijms22115684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198572PMC
May 2021

Target 5000: a standardized all-Ireland pathway for the diagnosis and management of inherited retinal degenerations.

Orphanet J Rare Dis 2021 05 5;16(1):200. Epub 2021 May 5.

Mater Clinical Ophthalmic Genetics Unit, Mater Misericordiae University Hospital, Dublin, Ireland.

Introduction: Inherited retinal degenerations (IRD) are rare genetic disorders with > 300 known genetic loci, manifesting variably progressive visual dysfunction. IRDs were historically underserved due to lack of effective interventions. Many novel therapies will require accurate diagnosis (phenotype and genotype), thus an efficient and effective pathway for assessment and management is required.

Methods: Using surveys of existing practice patterns and advice from international experts, an all-Ireland IRD service (Target 5000) was designed. Detailed phenotyping was followed by next generation genetic sequencing in both a research and accredited laboratory. Unresolved pedigrees underwent further studies (whole gene/whole exome/whole genome sequencing). Novel variants were interrogated for pathogenicity (cascade screening, in silico analysis, functional studies). A multidisciplinary team (MDT; ophthalmologists, physicians, geneticists, genetic counsellors) reconciled phenotype with genotype. A bespoke care plan was created for each patient comprising supports, existing interventions, and novel therapies/clinical trials.

Results And Discussion: Prior to Target 5000, a significant cohort of patients were not engaged with healthcare/support services due to lack of effective interventions. Pathogenic or likely pathogenic variants in IRD-associated genes were detected in 62.3%, with 11.6% having variants of unknown significance. The genotyping arm of Target 5000 allowed a 42.73% cost saving over independent testing, plus the value of MDT expertise/processing. Partial funding has transferred from charitable sources to government resources.

Conclusion: Target 5000 demonstrates efficacious and efficient clinical/genetic diagnosis, while discovering novel IRD-implicated genes/variants and investigating mechanisms of disease and avenues of intervention. This model could be used to develop similar IRD programmes in small/medium-sized nations.
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http://dx.doi.org/10.1186/s13023-021-01841-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097252PMC
May 2021

Management of significant secondary genetic findings in an ophthalmic genetics clinic.

Eye (Lond) 2021 May 3. Epub 2021 May 3.

Mater Clinical Ophthalmic Genetics Unit, Mater Misericordiae University Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1038/s41433-021-01557-3DOI Listing
May 2021

Measurement of the Fluctuations in the Number of Muons in Extensive Air Showers with the Pierre Auger Observatory.

Phys Rev Lett 2021 Apr;126(15):152002

Université Paris-Saclay, CNRS/IN2P3, IJCLab, Orsay, France.

We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultrahigh energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultrahigh energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop.
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http://dx.doi.org/10.1103/PhysRevLett.126.152002DOI Listing
April 2021