Publications by authors named "Rachel L Taylor"

20 Publications

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New variants and in silico analyses in GRK1 associated Oguchi disease.

Hum Mutat 2021 Feb 30;42(2):164-176. Epub 2020 Nov 30.

Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.

Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.
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http://dx.doi.org/10.1002/humu.24140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898643PMC
February 2021

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy.

Ophthalmology 2020 Nov 1. Epub 2020 Nov 1.

UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom; Section of Ophthalmology, King's College London, St. Thomas' Hospital, London, United Kingdom; Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2020.10.032DOI Listing
November 2020

Craniosynostosis-microphthalmia syndrome belongs to the spectrum of BCOR-related disorders.

Clin Genet 2020 10 3;98(4):413-415. Epub 2020 Aug 3.

Medical Genetics Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.

Craniosynostosis-microphthalmia linked to BCOR haploinsufficiency.
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http://dx.doi.org/10.1111/cge.13808DOI Listing
October 2020

Small Molecules Restore Bestrophin 1 Expression and Function of Both Dominant and Recessive Bestrophinopathies in Patient-Derived Retinal Pigment Epithelium.

Invest Ophthalmol Vis Sci 2020 05;61(5):28

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Purpose: Bestrophinopathies are a group of untreatable inherited retinal dystrophies caused by mutations in the retinal pigment epithelium (RPE) Cl- channel bestrophin 1. We tested whether sodium phenylbutyrate (4PBA) could rescue the function of mutant bestrophin 1 associated with autosomal dominant and recessive disease. We then sought analogues of 4PBA with increased potency and determined the mode of action for 4PBA and a lead compound 2-naphthoxyacetic acid (2-NOAA). Lastly, we tested if 4PBA and 2-NOAA could functionally rescue bestrophin 1 function in RPE generated from induced pluripotent stem cells (iPSC-RPEs) derived from patients with a dominant or recessive bestrophinopathy.

Methods: Global and plasma membrane expression was determined by Western blot and immunofluorescent microscopy, respectively. The effect of 4PBA and 2-NOAA on transcription was measured by quantitative RT-PCR and the rate of protein turnover by cycloheximide chase and Western blot. Channel function was measured by whole-cell patch clamp.

Results: 4PBA and 2-NOAA can rescue the global and membrane expression of mutant bestrophin 1 associated with autosomal dominant disease (Best vitelliform macular dystrophy [BVMD]) and autosome recessive bestrophinopathy (ARB), and these small molecules have different modes of action. Both 4PBA and 2-NOAA significantly increased the channel function of mutant BVMD and ARB bestrophin 1 in HEK293T and iPSC-RPE cells derived from patients with BVMD and ARB. For 4PBA, the increased mutant channel function in BVMD and ARB iPSC-RPE was equal to that of wild-type iPSC-RPE bestrophin 1.

Conclusions: The restoration of bestrophin 1 function in patient-derived RPE confirms the US Food and Drug Administration-approved drug 4PBA as a promising therapeutic treatment for bestrophinopathies.
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http://dx.doi.org/10.1167/iovs.61.5.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405785PMC
May 2020

Using an integrative machine learning approach utilising homology modelling to clinically interpret genetic variants: CACNA1F as an exemplar.

Eur J Hum Genet 2020 09 20;28(9):1274-1282. Epub 2020 Apr 20.

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Advances in DNA sequencing technologies have revolutionised rare disease diagnostics and have led to a dramatic increase in the volume of available genomic data. A key challenge that needs to be overcome to realise the full potential of these technologies is that of precisely predicting the effect of genetic variants on molecular and organismal phenotypes. Notably, despite recent progress, there is still a lack of robust in silico tools that accurately assign clinical significance to variants. Genetic alterations in the CACNA1F gene are the commonest cause of X-linked incomplete Congenital Stationary Night Blindness (iCSNB), a condition associated with non-progressive visual impairment. We combined genetic and homology modelling data to produce CACNA1F-vp, an in silico model that differentiates disease-implicated from benign missense CACNA1F changes. CACNA1F-vp predicts variant effects on the structure of the CACNA1F encoded protein (a calcium channel) using parameters based upon changes in amino acid properties; these include size, charge, hydrophobicity, and position. The model produces an overall score for each variant that can be used to predict its pathogenicity. CACNA1F-vp outperformed four other tools in identifying disease-implicated variants (area under receiver operating characteristic and precision recall curves = 0.84; Matthews correlation coefficient = 0.52) using a tenfold cross-validation technique. We consider this protein-specific model to be a robust stand-alone diagnostic classifier that could be replicated in other proteins and could enable precise and timely diagnosis.
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http://dx.doi.org/10.1038/s41431-020-0623-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608274PMC
September 2020

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders.

Genet Med 2020 04 18;22(4):745-751. Epub 2019 Dec 18.

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, UK.

Purpose: A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs).

Methods: Two hundred one unrelated children (0-5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011-2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing.

Results: The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism).

Conclusion: Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.
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http://dx.doi.org/10.1038/s41436-019-0722-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118019PMC
April 2020

Diagnostic yield of panel-based genetic testing in syndromic inherited retinal disease.

Eur J Hum Genet 2020 05 13;28(5):576-586. Epub 2019 Dec 13.

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre (MAHSC), University of Manchester, Manchester, UK.

Thirty percent of all inherited retinal disease (IRD) is accounted for by conditions with extra-ocular features. This study aimed to establish the genetic diagnostic pick-up rate for IRD patients with one or more extra-ocular features undergoing panel-based screening in a clinical setting. One hundred and six participants, tested on a gene panel which contained both isolated and syndromic IRD genes, were retrospectively ascertained from the Manchester Genomic Diagnostics Laboratory database spanning 6 years (2012-2017). Phenotypic features were extracted from the clinical notes and classified according to Human Phenotype Ontology; all identified genetic variants were interpreted in accordance to the American College of Medical Genetics and Genomics guidelines. Overall, 49% (n = 52) of patients received a probable genetic diagnosis. A further 6% (n = 6) had a single disease-associated variant in an autosomal recessive disease-relevant gene. Fifty-two percent (n = 55) of patients had a clinical diagnosis at the time of testing. Of these, 71% (n = 39) received a probable genetic diagnosis. By contrast, for those without a provisional clinical diagnosis (n = 51), only 25% (n = 13) received a probable genetic diagnosis. The clinical diagnosis of Usher (n = 33) and Bardet-Biedl syndrome (n = 10) was confirmed in 67% (n = 22) and 80% (n = 8), respectively. The testing diagnostic rate in patients with clinically diagnosed multisystemic IRD conditions was significantly higher than those without one (71% versus 25%; p value < 0.001). The lower pick-up rate in patients without a clinical diagnosis suggests that panel-based approaches are unlikely to be the most effective means of achieving a molecular diagnosis for this group. Here, we suggest that genome-wide approaches (whole exome or genome) are more appropriate.
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http://dx.doi.org/10.1038/s41431-019-0548-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171123PMC
May 2020

Loss-of-Function Mutations in the CFH Gene Affecting Alternatively Encoded Factor H-like 1 Protein Cause Dominant Early-Onset Macular Drusen.

Ophthalmology 2019 10 21;126(10):1410-1421. Epub 2019 Mar 21.

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester, United Kingdom. Electronic address:

Purpose: To characterize the molecular mechanism underpinning early-onset macular drusen (EOMD), a phenotypically severe subtype of age-related macular degeneration (AMD), in a subgroup of patients.

Design: Multicenter case series, in vitro experimentation, and retrospective analysis of previously reported variants.

Participants: Seven families with apparently autosomal dominant EOMD.

Methods: Patients underwent a comprehensive ophthalmic assessment. Affected individuals from families A, B, and E underwent whole exome sequencing. The probands from families C, D, F, and G underwent Sanger sequencing analysis of the complement factor H (CFH) gene. Mutant recombinant factor H like-1 (FHL-1) proteins were expressed in HEK293 cells to assess the impact on FHL-1 expression and function. Previously reported EOMD-causing variants in CFH were reviewed.

Main Outcome Measures: Detailed clinical phenotypes, genomic findings, in vitro characterization of mutation effect on protein function, and postulation of the pathomechanism underpinning EOMD.

Results: All affected participants demonstrated bilateral drusen. The earliest reported age of onset was 16 years (median, 46 years). Ultra-rare (minor allele frequency [MAF], ≤0.0001) CFH variants were identified as the cause of disease in each family: CFH c.1243del, p.(Ala415ProfsTer39) het; c.350+1G→T het; c.619+1G→A het, c.380G→A, p.(Arg127His) het; c.694C→T p.(Arg232Ter) het (identified in 2 unrelated families in this cohort); and c.1291T→A, p.(Cys431Ser). All mutations affect complement control protein domains 2 through 7, and thus are predicted to impact both FHL-1, the predominant isoform in Bruch's membrane (BrM) of the macula, and factor H (FH). In vitro analysis of recombinant proteins FHL-1, FHL-1, and FHL-1 demonstrated that they are not secreted, and thus are loss-of-function proteins. Review of 29 previously reported EOMD-causing mutations found that 75.8% (22/29) impact FHL-1 and FH. In total, 86.2% (25/29) of EOMD-associated variants cause haploinsufficiency of FH or FHL-1.

Conclusions: Early-onset macular drusen is an underrecognized, phenotypically severe subtype of AMD. We propose that haploinsufficiency of FHL-1, the main regulator of the complement pathway in BrM, where drusen develop, is an important mechanism underpinning the development of EOMD in a number of cases. Understanding the molecular basis of EOMD will shed light on AMD pathogenesis given their pathologic similarities.
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http://dx.doi.org/10.1016/j.ophtha.2019.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856713PMC
October 2019

Bi-allelic Loss-of-Function Variants in DNMBP Cause Infantile Cataracts.

Am J Hum Genet 2018 10;103(4):568-578

Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1205, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, Geneva 1211, Switzerland. Electronic address:

Infantile and childhood-onset cataracts form a heterogeneous group of disorders; among the many genetic causes, numerous pathogenic variants in additional genes associated with autosomal-recessive infantile cataracts remain to be discovered. We identified three consanguineous families affected by bilateral infantile cataracts. Using exome sequencing, we found homozygous loss-of-function variants in DNMBP: nonsense variant c.811C>T (p.Arg271) in large family F385 (nine affected individuals; LOD score = 5.18 at θ = 0), frameshift deletion c.2947_2948del (p.Asp983) in family F372 (two affected individuals), and frameshift variant c.2852_2855del (p.Thr951Metfs41) in family F3 (one affected individual). The phenotypes of all affected individuals include infantile-onset cataracts. RNAi-mediated knockdown of the Drosophila ortholog still life (sif), enriched in lens-secreting cells, affects the development of these cells as well as the localization of E-cadherin, alters the distribution of septate junctions in adjacent cone cells, and leads to a ∼50% reduction in electroretinography amplitudes in young flies. DNMBP regulates the shape of tight junctions, which correspond to the septate junctions in invertebrates, as well as the assembly pattern of E-cadherin in human epithelial cells. E-cadherin has an important role in lens vesicle separation and lens epithelial cell survival in humans. We therefore conclude that DNMBP loss-of-function variants cause infantile-onset cataracts in humans.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174361PMC
October 2018

GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay.

Hum Mol Genet 2019 01;28(1):96-104

Department of Pediatrics, University Medical Center Utrecht, Utrecht University, Utrecht CX, The Netherlands.

Loss-of-function mutations in glutaminase (GLS), the enzyme converting glutamine into glutamate, and the counteracting enzyme glutamine synthetase (GS) cause disturbed glutamate homeostasis and severe neonatal encephalopathy. We report a de novo Ser482Cys gain-of-function variant in GLS encoding GLS associated with profound developmental delay and infantile cataract. Functional analysis demonstrated that this variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS, supporting pathogenicity. Ser482Cys-GLS likely improves the electrostatic environment of the GLS catalytic site, thereby intrinsically inducing hyperactivity. Alignment of +/-12.000 GLS protein sequences from >1000 genera revealed extreme conservation of Ser482 to the same degree as catalytic residues. Together with the hyperactivity, this indicates that Ser482 is evolutionarily preserved to achieve optimal-but submaximal-GLS activity. In line with GLS hyperactivity, increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts. In the brain (both grey and white matter), glutamate was also extremely high and glutamine was almost undetectable, demonstrated with magnetic resonance spectroscopic imaging at clinical field strength and subsequently supported at ultra-high field strength. Considering the neurotoxicity of glutamate when present in excess, the strikingly high glutamate concentrations measured in the brain provide an explanation for the developmental delay. Cataract, a known consequence of oxidative stress, was evoked in zebrafish expressing the hypermorphic Ser482Cys-GLS and could be alleviated by inhibition of GLS. The capacity to detoxify reactive oxygen species was reduced upon Ser482Cys-GLS expression, providing an explanation for cataract formation. In conclusion, we describe an inborn error of glutamate metabolism caused by a GLS hyperactivity variant, illustrating the importance of balanced GLS activity.
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http://dx.doi.org/10.1093/hmg/ddy330DOI Listing
January 2019

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

Am J Hum Genet 2018 06 31;102(6):1195-1203. Epub 2018 May 31.

Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992133PMC
June 2018

Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases.

J Med Genet 2018 02 26;55(2):114-121. Epub 2017 Oct 26.

Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, St Mary's Hospital, Manchester, UK.

Background: Diagnostic use of gene panel next-generation sequencing (NGS) techniques is commonplace for individuals with inherited retinal dystrophies (IRDs), a highly genetically heterogeneous group of disorders. However, these techniques have often failed to capture the complete spectrum of genomic variation causing IRD, including CNVs. This study assessed the applicability of introducing CNV surveillance into first-tier diagnostic gene panel NGS services for IRD.

Methods: Three read-depth algorithms were applied to gene panel NGS data sets for 550 referred individuals, and informatics strategies used for quality assurance and CNV filtering. CNV events were confirmed and reported to referring clinicians through an accredited diagnostic laboratory.

Results: We confirmed the presence of 33 deletions and 11 duplications, determining these findings to contribute to the confirmed or provisional molecular diagnosis of IRD for 25 individuals. We show that at least 7% of individuals referred for diagnostic testing for IRD have a CNV within genes relevant to their clinical diagnosis, and determined a positive predictive value of 79% for the employed CNV filtering techniques.

Conclusion: Incorporation of CNV analysis increases diagnostic yield of gene panel NGS diagnostic tests for IRD, increases clarity in diagnostic reporting and expands the spectrum of known disease-causing mutations.
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http://dx.doi.org/10.1136/jmedgenet-2017-104791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800348PMC
February 2018

Validation of copy number variation analysis for next-generation sequencing diagnostics.

Eur J Hum Genet 2017 06 5;25(6):719-724. Epub 2017 Apr 5.

Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.

Although a common cause of disease, copy number variants (CNVs) have not routinely been identified from next-generation sequencing (NGS) data in a clinical context. This study aimed to examine the sensitivity and specificity of a widely used software package, ExomeDepth, to identify CNVs from targeted NGS data sets. We benchmarked the accuracy of CNV detection using ExomeDepth v1.1.6 applied to targeted NGS data sets by comparison to CNV events detected through whole-genome sequencing for 25 individuals and determined the sensitivity and specificity of ExomeDepth applied to these targeted NGS data sets to be 100% and 99.8%, respectively. To define quality assurance metrics for CNV surveillance through ExomeDepth, we undertook simulation of single-exon (n=1000) and multiple-exon heterozygous deletion events (n=1749), determining a sensitivity of 97% (n=2749). We identified that the extent of sequencing coverage, the inter- and intra-sample variability in the depth of sequencing coverage and the composition of analysis regions are all important determinants of successful CNV surveillance through ExomeDepth. We then applied these quality assurance metrics during CNV surveillance for 140 individuals across 12 distinct clinical areas, encompassing over 500 potential rare disease diagnoses. All 140 individuals lacked molecular diagnoses after routine clinical NGS testing, and by application of ExomeDepth, we identified 17 CNVs contributing to the cause of a Mendelian disorder. Our findings support the integration of CNV detection using ExomeDepth v1.1.6 with routine targeted NGS diagnostic services for Mendelian disorders. Implementation of this strategy increases diagnostic yields and enhances clinical care.
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http://dx.doi.org/10.1038/ejhg.2017.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427176PMC
June 2017

Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease.

Ophthalmology 2017 07 22;124(7):985-991. Epub 2017 Mar 22.

Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, School of Health Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.

Purpose: To assess the clinical usefulness of genetic testing in a pediatric population with inherited retinal disease (IRD).

Design: Single-center retrospective case series.

Participants: Eighty-five unrelated children with a diagnosis of isolated or syndromic IRD who were referred for clinical genetic testing between January 2014 and July 2016.

Methods: Participants underwent a detailed ophthalmic examination, accompanied by electrodiagnostic testing (EDT) and dysmorphologic assessment where appropriate. Ocular and extraocular features were recorded using Human Phenotype Ontology terms. Subsequently, multigene panel testing (105 or 177 IRD-associated genes) was performed in an accredited diagnostic laboratory, followed by clinical variant interpretation.

Main Outcome Measures: Diagnostic yield and clinical usefulness of genetic testing.

Results: Overall, 78.8% of patients (n = 67) received a probable molecular diagnosis; 7.5% (n = 5) of these had autosomal dominant disease, 25.4% (n = 17) had X-linked disease, and 67.2% (n = 45) had autosomal recessive disease. In a further 5.9% of patients (n = 5), a single heterozygous ABCA4 variant was identified; all these participants had a spectrum of clinical features consistent with ABCA4 retinopathy. Most participants (84.7%; n = 72) had undergone EDT and 81.9% (n = 59) of these patients received a probable molecular diagnosis. The genes most frequently mutated in the present cohort were CACNA1F and ABCA4, accounting for 14.9% (n = 10) and 11.9% (n = 8) of diagnoses respectively. Notably, in many cases, genetic testing helped to distinguish stationary from progressive IRD subtypes and to establish a precise diagnosis in a timely fashion.

Conclusions: Multigene panel testing pointed to a molecular diagnosis in 84.7% of children with IRD. The diagnostic yield in the study population was significantly higher compared with that in previously reported unselected IRD cohorts. Approaches similar to the one described herein are expected to become a standard component of care in pediatric ophthalmology. We propose the introduction of genetic testing early in the diagnostic pathway in children with clinical and/or electrophysiologic findings, suggestive of IRD.
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http://dx.doi.org/10.1016/j.ophtha.2017.02.005DOI Listing
July 2017

Association of Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation With Early-Onset Retinal Dystrophy.

JAMA Ophthalmol 2017 04;135(4):339-347

Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, England2Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, England.

Importance: Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare disorder of N-linked glycosylation. Its retinal phenotype is not well described but could be important for disease recognition because it appears to be a consistent primary presenting feature.

Objective: To investigate a series of patients with the same mutation in the SRD5A3 gene and thereby characterize its retinal manifestations and other associated features.

Design, Setting And Participants: Seven affected individuals from 4 unrelated families with early-onset retinal dystrophy as a primary manifestation underwent comprehensive ophthalmic assessment, including retinal imaging and electrodiagnostic testing. Developmental and systemic findings were also recorded. Molecular genetic approaches, including targeted next-generation sequencing, autozygosity mapping, and apex microarray, were tried to reach a diagnosis; all participants were mutation negative. Whole-exome sequencing or whole-genome sequencing was used to identify the causative variant. Biochemical profiling was conducted to confirm a CDG type I defect. Patient phenotype data were collected over the course of ophthalmic follow-up, spanning a period of 20 years, beginning March 20, 1997, through September 15, 2016.

Main Outcomes And Measures: Detailed clinical phenotypes as well as genetic and biochemical results.

Results: The cohort consisted of 7 participants (5 females and 2 males) whose mean (SD) age at the most recent examination was 17.1 (3.9) years and who were all of South Asian ethnicity. Whole-exome sequencing and whole-genome sequencing identified the same homozygous SRD5A3 c.57G>A, p.(Trp19Ter) variant as the underlying cause of early-onset retinal dystrophy in each family. Detailed ocular phenotyping identified early-onset (aged ≤3 years) visual loss (mean [SD] best-corrected visual acuity, +0.95 [0.34] logMAR [20/180 Snellen]), childhood-onset nyctalopia, myopia (mean [SD] refractive error, -6.71 [-4.22]), and nystagmus. Six of the 7 patients had learning difficulties and psychomotor delay. Fundus autofluorescence imaging and optical coherence tomographic scans were abnormal in all patients, and electrodiagnostic testing revealed rod and cone dysfunction in the 5 patients tested.

Conclusions And Relevance: Mutations in the SRD5A3 gene may cause early-onset retinal dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment. SRD5A3 and other glycosylation disorder genes should be considered as a cause of retinal dystrophy even when systemic features are mild. Further delineation of SRD5A3-associated eye phenotypes can help inform genetic counseling for prognostic estimation of visual loss and disease progression.
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http://dx.doi.org/10.1001/jamaophthalmol.2017.0046DOI Listing
April 2017

Novel PEX11B Mutations Extend the Peroxisome Biogenesis Disorder 14B Phenotypic Spectrum and Underscore Congenital Cataract as an Early Feature.

Invest Ophthalmol Vis Sci 2017 01;58(1):594-603

Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, The University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom 3Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, United Kingdom.

Purpose: Peroxisomes perform complex metabolic and catabolic functions essential for normal growth and development. Mutations in 14 genes cause a spectrum of peroxisomal disease in humans. Most recently, PEX11B was associated with an atypical peroxisome biogenesis disorder (PBD) in a single individual. In this study, we identify further PEX11B cases and delineate associated phenotypes.

Methods: Probands from three families underwent next generation sequencing (NGS) for diagnosis of a multisystem developmental disorder. Autozygosity mapping was conducted in one affected sibling pair. ExomeDepth was used to identify copy number variants from NGS data and confirmed by dosage analysis. Biochemical profiling was used to investigate the metabolic signature of the condition.

Results: All patients presented with bilateral cataract at birth but the systemic phenotype was variable, including short stature, skeletal abnormalities, and dysmorphism-features not described in the original case. Next generation sequencing identified biallelic loss-of-function mutations in PEX11B as the underlying cause of disease in each case (PEX11B c.235C>T p.(Arg79Ter) homozygous; PEX11B c.136C>T p.(Arg46Ter) homozygous; PEX11B c.595C>T p.(Arg199Ter) heterozygous, PEX11B ex1-3 del heterozygous). Biochemical studies identified very low plasmalogens in one patient, whilst a mildly deranged very long chain fatty acid profile was found in another.

Conclusions: Our findings expand the phenotypic spectrum of the condition and underscore congenital cataract as the consistent primary presenting feature. We also find that biochemical measurements of peroxisome function may be disturbed in some cases. Furthermore, diagnosis by NGS is proficient and may circumvent the requirement for an invasive skin biopsy for disease identification from fibroblast cells.
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http://dx.doi.org/10.1167/iovs.16-21026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841568PMC
January 2017

Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.

Arch Neurol 2008 Jan 12;65(1):45-53. Epub 2007 Nov 12.

GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Objective: To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs.

Design: Case-control study with replication.

Setting: Memory referral clinics in Canada and the United Kingdom.

Participants: The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England.

Main Outcome Measures: Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments.

Results: Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P< .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2).

Conclusions: Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.
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http://dx.doi.org/10.1001/archneurol.2007.3DOI Listing
January 2008

Characteristics of smokers with a psychotic disorder and implications for smoking interventions.

Psychiatry Res 2007 Mar 7;150(2):141-52. Epub 2007 Feb 7.

Centre for Mental Health Studies, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.

Despite high rates of smoking among people with psychotic disorders, and the associated health and financial burden, few studies have investigated the characteristics of this group of smokers. This paper reports data from 298 smokers with an ICD-10 psychotic disorder residing in the community (56.7% with schizophrenia or schizoaffective disorder), including an examination of their demographic and clinical characteristics, smoking behaviours, severity of nicotine dependence, stage of change, and reasons for smoking and for quitting. Standardized self-report instruments were used, in conjunction with structured interviews, as part of the first phase of a randomized controlled trial. On average, participants smoked 30 cigarettes per day, commenced smoking daily at about 18 years of age (5 years before illness onset), and had made 2-3 quit attempts in their lifetime. Higher levels of nicotine dependence and concurrent hazardous use of alcohol or cannabis were associated with a younger age at smoking initiation. The present sample was also more likely to report stress reduction, stimulation and addiction as reasons for smoking, compared to a general sample of smokers. Males, precontemplators and participants with concurrent hazardous substance use cited fewer reasons for quitting smoking. These and other subgroup differences in smoking characteristics are used to illustrate potential implications for the nature and timing of smoking interventions among people with a psychotic disorder.
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http://dx.doi.org/10.1016/j.psychres.2006.05.021DOI Listing
March 2007

A randomized controlled trial of a smoking cessation intervention among people with a psychotic disorder.

Am J Psychiatry 2006 Nov;163(11):1934-42

Centre for Mental Health Studies, University of Newcastle, University Dr., Callaghan, NSW 2308, Australia.

Objective: Despite extremely high rates of smoking among individuals with psychotic disorders and the associated financial and health costs, few studies have investigated the efficacy of smoking cessation interventions among this group. The purpose of this study was to compare an integrated psychological and nicotine replacement therapy intervention for people with a psychotic disorder with routine care alone.

Method: The authors recruited 298 regular smokers with a psychotic disorder residing in the community and randomly assigned them to a routine care comparison condition (N=151) or an eight-session, individually administered smoking cessation intervention (N=147), which consisted of nicotine replacement therapy, motivational interviewing, and cognitive behavior therapy. Outcome variables included continuous and point-prevalence abstinence rates, smoking reduction status, and changes in symptoms and functioning.

Results: While there were no overall differences between the treatment group and comparison group in abstinence rates, a significantly higher proportion of smokers who completed all treatment sessions stopped smoking at each of the follow-up occasions (point-prevalence rates: 3 months, 30.0% versus 6.0%; 6 months, 18.6% versus 4.0%; and 12 months, 18.6% versus 6.6%). Smokers who completed all treatment sessions were also more likely to have achieved continuous abstinence at 3 months (21.4% versus 4.0%). There was a strong dose-response relationship between treatment session attendance and smoking reduction status, with one-half of those who completed the intervention program achieving a 50% or greater reduction in daily cigarette consumption across the follow-ups, relative to less than one-fifth of the comparison subjects. There was no evidence of any associated deterioration in symptoms or functioning.

Conclusions: These findings demonstrate the utility of a nicotine replacement therapy plus motivational interviewing/cognitive behavior therapy smoking cessation intervention among individuals with a psychotic disorder. Further development of more efficacious interventions is required for those who do not respond to existing interventions.
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http://dx.doi.org/10.1176/ajp.2006.163.11.1934DOI Listing
November 2006