Publications by authors named "Penny Clouston"

27 Publications

  • Page 1 of 1

Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL.

Genes (Basel) 2020 Dec 12;11(12). Epub 2020 Dec 12.

Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, Level 6 John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.

Autosomal recessive retinitis pigmentosa is caused by mutations in over 40 genes, one of which is the ceramide kinase-like gene (). We present a case series of six patients from six unrelated families diagnosed with inherited retinal dystrophies (IRD) and with two variants in recruited from a multi-ethnic British population. A retrospective review of clinical data in these patients was performed and included colour fundus photography, fundus autofluorescence (AF) imaging, spectral domain-optical coherence tomography (SD-OCT), visual fields and electroretinogram (ERG) assessment where available. Three female and three male patients were included. Age at onset ranged from 7 years old to 45 years, with three presenting in their 20s and two presenting in their 40s. All but one had central visual loss as one of their main presenting symptoms. Four patients had features of retinitis pigmentosa with significant variation in severity and extent of disease, and two patients had no pigment deposition with only macular involvement clinically. Seven variants in were identified, of which three are novel. The inherited retinopathies associated with the gene vary in age at presentation and in degree of severity, but generally are characterised by a central visual impairment early on.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11121497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763961PMC
December 2020

Novel Pathogenic Sequence Variants in and Clinical Findings in Three Patients.

Genes (Basel) 2020 Oct 29;11(11). Epub 2020 Oct 29.

Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.

A retrospective review of the clinical records of patients seen at the Oxford Eye Hospital identified as having mutations was performed. The data included symptoms, best-corrected visual acuity, multimodal retinal imaging, visual fields and electrophysiology testing. Three participants were identified with biallelic pathogenic sequence variants detected using a targeted NGS gene panel, two of which were novel. Participant I was a Nepalese male aged 68 years, and participants II and III were white Caucasian females aged 69 and 10 years old, respectively. All three had childhood onset nyctalopia, a progressive decrease in central vision, and visual field loss. Patients I and III had photopsia, patient II had photosensitivity and patient III also had photophobia. Visual acuities in patients I and II were preserved even into the seventh decade, with the worst visual acuity measured at 6/36. Visual field constriction was severe in participant I, less so in II, and fields were full to bright targets targets in participant III. Electrophysiology testing in all three demonstrated loss of rod function. The three patients share some of the typical distinctive features of retinopathies, as well as a novel clinical observation of foveal ellipsoid thickening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11111288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716234PMC
October 2020

Association of a Novel Intronic Variant in RPGR With Hypomorphic Phenotype of X-Linked Retinitis Pigmentosa.

JAMA Ophthalmol 2020 Sep 24. Epub 2020 Sep 24.

Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, England.

Importance: Pathogenic variants in retinitis pigmentosa GTPase regulator (RPGR) gene typically lead to a severe form of X-linked retinitis pigmentosa, which is associated with early severe vision loss.

Objective: To investigate an X-linked retinal degeneration family with atypical preservation of visual acuity in the presence of a novel deep intronic splice site RPGR c.779-5T>G variant.

Design, Setting, And Participants: In this case series, 3 members of an X-linked retinal degeneration family were studied by in-depth phenotyping and genetic screening at a single center. Data were collected and analyzed from November 2018 to March 2020.

Main Outcomes And Measures: Data were collected on full ophthalmic history, examination, and retinal imaging. A full retinitis pigmentosa gene panel was analyzed by next-generation sequencing. The pathogenicity of the RPGR c.779-5T>G variant was assessed by in silico splice prediction tools and by purpose-designed in vitro splicing assay.

Results: An 84-year-old man was referred with clinical diagnosis of choroideremia and possible inclusion into a gene therapy trial. He presented with late-stage retinal degeneration and unusually preserved visual acuity (78 and 68 ETRDS letters) that clinically resembled choroideremia. His 23-year-old grandson was still in early stages of degeneration but showed a very different clinical picture, typical of retinitis pigmentosa. Next-generation sequencing identified a sole RPGR c.779-5T>G variant of undetermined pathogenicity in both cases. The daughter of the proband showed an RPGR carrier phenotype and was confirmed to carry the same variant. The molecular analysis confirmed that the RPGR c.779-5T>G variation reduced the efficiency of intron splicing compared with wild type, leading to a population of mutant and normal transcripts. The predicted consequences of the pathogenic variant are potential use of an alternative splice acceptor site or complete skipping of exon 8, resulting in truncated forms of the RPGR protein with different levels of glutamylation.

Conclusions And Relevance: These results support the importance of careful interpretation of inconsistent clinical phenotypes between family members. Using a molecular splicing assay, a new pathogenic variant in a noncoding region of RPGR was associated with a proportion of normal and hypomorphic RPGR, where cones are likely to survive longer than expected, potentially accounting for the preserved visual acuity observed in this family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2020.3634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516822PMC
September 2020

"Genetic and clinical findings in an ethnically diverse retinitis pigmentosa cohort associated with pathogenic variants in EYS".

Eye (Lond) 2020 Jul 29. Epub 2020 Jul 29.

Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Headley Way, Oxford, OX3 9DU, UK.

Background And Objectives: The EYS gene is an important cause of autosomal recessive retinitis pigmentosa (arRP). The objective of this study is to report on novel pathogenic variants in EYS and the range of associated phenotypes.

Subjects And Methods: This retrospective case series at a tertiary referral centre for inherited retinal diseases describes patients with an IRD and at least two variants in the EYS gene. Phenotyping included multimodal retinal imaging; genotyping molecular genetic analysis using targeted next generation sequencing. Sanger sequencing verification and analysis of novel variants using in silico approaches to determine their predicted pathogenicity.

Results: Eight male and four female patients were included. Age at onset ranged from 11 to 62 years with variable symptom presentation; ten patients showed classical features of retinitis pigmentosa, albeit with great variation in disease severity and extent. Two patients had atypical phenotypes: one with localised inferior sector pigmentation and a mild RP phenotype with changes predominantly at the posterior pole. Eighteen variants in EYS were identified, located across the gene: six were novel. Eight variants were missense, two altered splicing, one was a whole exon duplication and the remainder were predicted to result in premature truncation of the protein.

Conclusion: The marked variability in severity and age of onset in most patients in this ethnically diverse cohort adds to growing evidence that that mild phenotypes are associated with EYS variants. Similarly, the two atypical cases add to the growing diversity of EYS disease as do the six novel pathogenic variants described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41433-020-1105-8DOI Listing
July 2020

Next generation sequencing using phenotype-based panels for genetic testing in inherited retinal diseases.

Ophthalmic Genet 2020 08 16;41(4):331-337. Epub 2020 Jun 16.

Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford, UK.

Introduction: Diagnostic next generation sequencing (NGS) services for patients with inherited retinal diseases (IRD) traditionally use gene panel based approaches, which have cost and resource implications. Phenotype-based gene panels use a targeted strategy with further testing protocols, if initial results are negative. We present the molecular findings of the Oxford phenotype-based NGS panels for genetic testing in IRD.

Methods: Results of 655 consecutive patients referred for phenotype-based panel testing over 54 months were analysed to assess diagnostic yield.

Results: Variants were identified in 450 patients (68.7%). The overall diagnostic yield from phenotype-based panels was 42.8%. The diagnostic yield was highest from panels representing distinct clinical phenotypes: Usher panel 90.9% and congenital stationary night blindness panel 75.0%. Retinitis pigmentosa/rod-cone dystrophy was the commonest presenting phenotype (n = 243) and Usher syndrome was the commonest presenting syndromic disease (n = 39). Patients presenting with late-onset (≥50 years) macular disease had a lower diagnostic yield (18.0%) compared with patients <50 years (24.2%). Additionally, a diagnostic yield of 1.8% was attributable to copy number variants.

Conclusions: Phenotype-based genetic testing panels provide a targeted testing approach and reduce bioinformatics demand. The overall diagnostic yield achieved in this study reflects the wide range of phenotypes that were referred. This pragmatic approach provides a high yield for early-onset and clearly defined genetically determined disorders but clinical utility is not as clear for late-onset macular disorders. This phenotype-based panel approach is clinician-referrer orientated, and can be used as a front-end virtual panel, when whole genome sequencing is introduced into diagnostic services for IRD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13816810.2020.1778736DOI Listing
August 2020

Association of Clinical and Genetic Heterogeneity With BEST1 Sequence Variations.

JAMA Ophthalmol 2020 05;138(5):544-551

Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Importance: Detailed phenotypic information on the spectrum of fundus abnormalities and clinical variability of all phenotypes associated with sequence variations in BEST1 is limited.

Objective: To report a detailed phenotypic and genetic analysis of a patient cohort with sequence variations in BEST1.

Design, Setting, And Participants: This retrospective case series took place at the Oxford Eye Hospital in Oxford, UK. Thirty-six patients from a single center with disease-causing sequence variations in BEST1 from 25 different families were analyzed. Data were collected from November 2017 to June 2018, and analysis began April 2018.

Main Outcomes And Measures: Results of ocular phenotyping and genetic testing using targeted next-generation sequencing to identify BEST1 sequence variations.

Results: Thirty-six patients from 25 families with disease-causing sequence variations in BEST1 were included. Of 36 patients, 20 (55.6%) were female. Three distinct clinical phenotypes were identified: autosomal recessive bestrophinopathy (ARB), best vitelliform macular dystrophy (BVMD), and adult-onset vitelliform macular dystrophy. The ARB phenotype group comprised 18 patients from 9 families with age in years at symptom onset ranging from less than 10 to 40s. All patients showed a common phenotype of fundus autofluorescence abnormalities, and spectral-domain optical coherence tomography features were similar in all patients with schitic and cystoid changes. A phenotype of a beaten metallic retinal appearance extending from the mid periphery to the far periphery was identified in 8 patients. Four patients from 1 family with ARB were previously reported to have autosomal recessive retinitis pigmentosa but were reclassified as having ARB as part of this study. The BVMD phenotype group comprised 16 patients from 14 families with age at symptom onset ranging from less than 10 to 70s. Fundus features were localized to the macula and consistent with the stage of BVMD. In the adult-onset vitelliform macular dystrophy phenotype group, the age in years at symptom onset varied from 50s to 70s in 2 patients from 2 families. Fundus features included small vitelliform lesions. Where available, electro-oculogram results demonstrated a reduced or absent light rise in all patients with ARB and BVMD. Genetic testing identified 22 variants in BEST1.

Conclusions And Relevance: These findings support the notion that ARB, BVMD, and adult-onset vitelliform macular dystrophy are clinically distinct and recognizable phenotypes and suggest that the association of autosomal recessive retinitis pigmentosa with sequence variations in BEST1 should be rereviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2020.0666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118667PMC
May 2020

Association of Messenger RNA Level With Phenotype in Patients With Choroideremia: Potential Implications for Gene Therapy Dose.

JAMA Ophthalmol 2020 02;138(2):128-135

Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Importance: Gene therapy is a promising treatment for choroideremia, an X-linked retinal degeneration. The required minimum level of gene expression to ameliorate degeneration rate is unknown. This can be interrogated by exploring the association between messenger RNA (mRNA) levels and phenotype in mildly affected patients with choroideremia.

Objective: To analyze CHM mRNA splicing outcomes in 2 unrelated patients with the same c.940+3delA CHM splice site variant identified as mildly affected from a previous study of patients with choroideremia.

Design, Setting, And Participants: In this retrospective observational case series, 2 patients with c.940+3delA CHM variants treated at a single tertiary referral center were studied. In addition, a third patient with a c.940+2T>A variant that disrupts the canonical dinucleotide sequence at the same donor site served as a positive control. Data were collected from October 2013 to July 2018.

Main Outcomes And Measures: Central area of residual fundus autofluorescence was used as a biomarker for disease progression. CHM transcript splicing was assessed by both end point and quantitative polymerase chain reaction. Rab escort protein 1 (REP1) expression was assessed by immunoblot.

Results: The 2 mildly affected patients with c.940+3delA variants had large areas of residual autofluorescence for their age and longer degeneration half-lives compared with the previous cohort of patients with choroideremia. The control patient with a c.940+2T>A variant had a residual autofluorescence area within the range expected for his age. Both patients with the c.940+3delA variant expressed residual levels of full-length CHM mRNA transcripts relative to the predominant truncated transcript (mean [SEM] residual level: patient 1, 2.3% [0.3]; patient 2, 4.7% [0.2]), equivalent to approximately less than 1% of the level of full-length CHM expressed in nonaffected individuals. Full-length CHM expression was undetectable in the control patient. REP1 expression was less than the threshold for detection both in patients 1 and 2 and the control patient compared with wild-type controls.

Conclusions And Relevance: These results demonstrate the first genotype-phenotype association in choroideremia. A +3 deletion in intron 7 is sufficient to cause choroideremia in a milder form. If replicated with gene therapy, these findings would suggest that relatively low expression (less than 1%) of the wild-type levels of mRNA would be sufficient to slow disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2019.5071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990656PMC
February 2020

Infantile Onset of Spinocerebellar Ataxia Type 5 (SCA-5) in a 6 Month Old with Ataxic Cerebral Palsy.

Cerebellum 2020 Feb;19(1):161-163

Departments of Genetic Medicine, Regional Genetics Centre, Belfast Health and Social Care Trust, A Floor, Belfast HSC Trust, Belfast, BT9 7AB, UK.

Spinocerebellar ataxia type 5 (SCA-5) is a predominantly slowly progressive adult onset ataxia. We describe a child with a presentation of ataxic cerebral palsy (CP) and developmental delay at 6 months of age. Genetic testing confirmed a c.812C>T p.(Thr271Ile) mutation within the SPTBN2 gene. Seven previous cases of infantile onset SCA-5 are reported in the literature, four of which had a CP presentation. Early onset of SCA-5 presents with ataxic CP and is a rare cause of cerebral palsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-019-01085-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978426PMC
February 2020

Presence of corneal crystals confirms an unusual presentation of Bietti's retinal dystrophy.

Ophthalmic Genet 2019 10 22;40(5):461-465. Epub 2019 Oct 22.

Nuffield Laboratory of Ophthalmology, University of Oxford & Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

: Bietti crystalline corneoretinal dystrophy (BCD) (OMIM 210370) is a rare autosomal recessive retinal dystrophy typically characterized by multiple intraretinal crystals over the posterior pole of the retina. Degeneration of the retina and sclerosis of the choroidal vessels results in progressive night blindness and central visual field loss.: Detailed ophthalmic and genetic testing of the patient and his father were performed.: We report on a 41-year-old male patient with advanced chorioretinal dystrophy at the posterior pole extending into the peripheral retina. His sister and his father were similarly affected with nyctalopia and decreased visual acuity, although his father had a milder phenotype of a typical macular dystrophy. On close slit-lamp examination, however, both patient and his father had multiple yellow-white crystals in the peripheral cornea. Corneal findings and consanguinity of the patient's parents lead to suspicion of BCD. Molecular genetic results of the patient and his father showed homozygous for CYP4V2, c. 197T>G p.(Met66Arg) confirming the diagnosis of BCD.: The patient's pedigree shows pseudodominant inheritance due to consanguineous parents. However, careful examination of the corneal findings strengthened the clinical suspicion of BCD, facilitating the molecular genetic confirmation of this autosomal recessive disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13816810.2019.1678176DOI Listing
October 2019

Clinical Characterization of Retinitis Pigmentosa Associated With Variants in SNRNP200.

JAMA Ophthalmol 2019 Sep 5. Epub 2019 Sep 5.

Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, Oxford University, John Radcliffe Hospital, Oxford, United Kingdom.

Importance: SNRNP200 is a recently identified genetic cause of autosomal dominant retinitis pigmentosa (RP). However, the associated retinal phenotype is not well characterized.

Objective: To describe the retinal phenotype in patients with RP secondary to variants in SNRNP200.

Design, Setting, And Participants: This retrospective, case-series study was performed at 2 tertiary referral centers for inherited retinal diseases. Participants included 9 consecutive patients from 8 families with RP attributed to variants in SNRNP200. Data were collected from August 2017 to March 2018 and analyzed from May to July 2018.

Main Outcomes And Measures: Results of clinical evaluation, multimodal retinal imaging, and molecular genetic testing using targeted next-generation sequencing.

Results: Of the 9 patients included in the analysis (4 female and 5 male; mean [SD] age at presentation, 19 [15] years), each presented with nyctalopia, typically in the first 2 decades of life, although 2 patients experienced symptom onset in middle age. None had any consistent systemic features suggestive of syndromic RP. Retinal imaging studies and electroretinography findings were typical of a rod-predominant dystrophy with later involvement of cone photoreceptors. Phenotypic heterogeneity was typified by 4 unrelated patients with the common c.2041C>T SNRNP200 variant who demonstrated a variable age of disease onset (middle teenage years to the fourth decade of life). Disease progression was slow, with all but 1 patient maintaining visual acuity of better than 20/40 in the better-seeing eye in the fifth and sixth decades of life.

Conclusions And Relevance: These data suggest that variants in SNRNP200 result in nonsyndromic RP with a typical phenotype of a rod-predominant dystrophy. Significant phenotypic heterogeneity and nonpenetrance were noted within some affected families. Symptom onset was typically within the first 2 decades of life, with slow progression and well-preserved visual acuities into the fifth and sixth decades.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2019.3298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735424PMC
September 2019

Clinical and Molecular Characterization of PROM1-Related Retinal Degeneration.

JAMA Netw Open 2019 06 5;2(6):e195752. Epub 2019 Jun 5.

Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom.

Importance: The PROM1 gene, commonly associated with cone-rod dystrophies, may have dominant or recessive phenotypes that influence disease onset and severity.

Objective: To characterize the clinical phenotype and molecular genetic variations in patients with PROM1 variants.

Design, Setting, And Participants: This case-series study was conducted at 2 specialist retinal genetics clinics and examined 19 consecutively enrolled patients with PROM1-related retinal degeneration. Data were collected and analyzed from May 2018 to December 2018.

Main Outcomes And Measures: Results of ophthalmic examination, retinal imaging, and molecular genetic analysis by next-generation sequencing.

Results: Of 19 patients, 13 (68%) were women, and age ranged from 11 to 70 years. All patients presented with central visual loss, with or without photophobia. Individuals with recessive variants commonly had severe loss of visual acuity by their 20s, whereas the dominant variant was associated with a milder phenotype, with most patients retaining good vision into late adulthood. The recessive cases were associated with a panretinal dystrophy of cone-rod phenotype with early macular involvement, whereas the dominant variants were associated with a cone-rod phenotype that was restricted to the macula with predominantly cone dysfunction. Next-generation sequencing identified 3 novel and 9 previously reported variants in PROM1. Recessive mutations included 6 truncating variants (3 nonsense and 3 frameshift), 4 splice site variants, and 1 missense variant. All 6 dominant variants were associated with a c.1117C>T missense variant. The variants were distributed throughout the PROM1 genomic sequence with no specific clustering on protein domains.

Conclusions And Relevance: In this case-series study, PROM1 recessive variants were associated with early-onset, severe panretinal degeneration. The similar phenotypes observed in patients with homozygous missense variants and splice site variants compared with similarly aged patients with truncating variants suggests that all recessive variants have a null (or loss of function close to null) outcome on PROM1 function. In contrast, the dominant missense cases were associated with a milder, cone-driven phenotype, suggesting that the dominant disease is preferentially associated with cones. This has implications for the development of treatments for this severely blinding disease, and adeno-associated viral vector-based gene therapy and optogenetics could become successful treatment options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2019.5752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6575153PMC
June 2019

The Location of Exon 4 Mutations in RP1 Raises Challenges for Genetic Counseling and Gene Therapy.

Am J Ophthalmol 2019 06 4;202:23-29. Epub 2019 Feb 4.

Oxford University Hospitals NHS Foundation Trust and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom.

Purpose: Mutations in the photoreceptor gene RP1 lead to recessive or dominantly inherited retinitis pigmentosa (RP). Since the dominantly inherited phenotype is generally milder than recessive cases, it raises the possibility that it could arise by haploinsufficiency; however, most mutations are in the terminal exon 4, which would be predicted to generate truncated proteins. We therefore assessed a cohort of RP patients with confirmed mutations in RP1 to examine the genetic basis of the exon 4 mutations.

Design: Observational case series.

Methods: A retrospective review of 15 patients, aged between 36 and 84, with RP1 mutations in exon 4 confirmed by Sanger sequencing. All patients underwent full ophthalmic examination.

Results: Two patients had homozygous mutations in RP1, p.(Glu1526*) and p.(Ser486fs), and presented with severe early-onset retinal degeneration. Their first-degree relatives were unaffected. Thirteen patients had dominantly inherited RP presenting in adult life with a rod-cone dystrophy phenotype. Four novel mutations were identified. All mutations were predicted to produce truncated RP1 protein of variable lengths, as follows: p.(Arg677*), p.(Gln679*), p.(Leu722*), p.(Ile725Argfs*6), p.(Ser734*)x2, p.(Leu762Tyrfs*17)x2, p.(Leu866Lysfs*7)x2, p.(Arg872Thrfs*2)x2, and p.(Gln917*).

Conclusion: The RP1 protein with a predicted length between 677 and 917 amino acids seems to have a dominant negative effect, whereas proteins shorter (486 amino acids) or longer than this (1526 amino acids) lead to a more severe phenotype, but only in homozygous individuals. Since mutations at various points along exon 4 have divergent consequences, genetic testing alone may be insufficient for counseling, but recessive inheritance should be considered likely in severe early-onset cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajo.2019.01.027DOI Listing
June 2019

Atypical choroideremia presenting with early-onset macular atrophy.

Acta Ophthalmol 2019 Sep 28;97(6):633-636. Epub 2019 Jan 28.

Oxford Eye Hospital, John Radcliffe, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Choroideremia is an X-linked recessive retinal degeneration predominantly affecting hemizygous males. It is caused by mutations in the CHM gene that encodes the Rab escort protein-1. Characteristic features include early nyctalopia followed by progressive constriction of peripheral visual fields and sparing of the central vision until late in life with a distinct fundoscopic appearance. We present the case of a 17-year-old male with a c.282delT in exon 4 of CHM that has not previously been reported. Phenotypically this patient presented with an atypical choroideremia phenotype of early central macular degeneration in addition to the classic peripheral fundus characteristic findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aos.14025DOI Listing
September 2019

Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing their Potential for Retinal Gene Therapy.

Genes (Basel) 2018 Dec 18;9(12). Epub 2018 Dec 18.

Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.

Inherited retinal degenerations are the leading cause of blindness in the working population. X-linked retinitis pigmentosa (XLRP), caused by mutations in the Retinitis pigmentosa GTPase regulator () gene is one of the more severe forms, and female carriers of mutations have a variable presentation. A retrospective review of twenty-three female carriers aged between 8 and 76 years old was carried out using fundoscopy, autofluorescence imaging (AF), blue reflectance (BR) imaging and optical coherence tomography (OCT). Confirmation of the genetic mutation was obtained from male relatives or Sanger genetic sequencing. Fundus examination and AF demonstrate phenotypic variability in carriers. The genetic mutation appears indeterminate of the degree of change. We found four distinct classifications based on AF images to describe carriers; normal (N) representing normal or near-normal AF appearance ( = 1, 4%); radial (R) pattern reflex without pigmentary retinopathy ( = 14, 61%); focal (F) pigmentary retinopathy ( = 5, 22%) and; male (M) phenotype ( = 3, 13%). The phenotypes were precisely correlated in both eyes (rs = 1.0, < 0.0001). Skewed X-inactivation can result in severely affected carrier females-in some cases indistinguishable from the male pattern and these patients should be considered for gene therapy. In the cases of the male (M) phenotype where the X-inactivation was skewed, the pattern was similar in both eyes, suggesting that the mechanism is not truly random but may have an underlying genetic basis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes9120643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316369PMC
December 2018

Electrophysiological verification of enhanced S-cone syndrome caused by a novel c.755T>C NR2E3 missense variant.

Ophthalmic Genet 2019 02 23;40(1):29-33. Epub 2018 Nov 23.

a Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences , Oxford University , Oxford , UK.

Background: Nuclear hormone receptor gene, NR2E3, plays a critical role in retinogenesis and determination of the rod photoreceptor phenotype. Mutations in NR2E3 typically lead to recessive enhanced S-cone syndrome (ESCS), where affected individuals show higher sensitivity to short wavelength light and early onset rod dysfunction. Patients with ESCS present in early childhood with nyctalopia, enhanced sensitivity to blue light and display a very heterogeneic retinal phenotype with varying degrees of clumped pigmentation and occasional retinoschisis.

Purpose: To confirm the pathogenicity of a novel mutation in NR2E3 using electrophysiological studies.

Materials And Methods: Patient underwent detailed clinical evaluation and ophthalmic imaging followed by next generation sequencing analysis and electrophysiological studies.

Results: We describe a case of a young man of Greek descent with a family history of retinal degeneration. His fundal features at presentation were atypical of ESCS, with striking macular involvement in both eyes, including fibrotic subretinal material overlying the pigment epithelial detachment in one eye and schisis in the other. Genetic testing revealed a novel homozygous variant in NR2E3 gene of uncertain pathogenicity. Instead of performing further genetic analyses, electrophysiological studies showed pathognomonic changes in the S-cone response.

Conclusions: With the recent clinical endorsement of a gene therapy for RPE65 related-inherited retinal degeneration it is of paramount importance to correctly identify the pathogenic genetic mutation. In this particular syndrome, we highlight the value of electrophysiology to confirm the pathogenicity of a novel mutation in NR2E3 and aid the diagnosis of ESCS, with potential for gene therapy in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13816810.2018.1547912DOI Listing
February 2019

Slowly progressive retinitis pigmentosa caused by two novel mutations in the MAK gene.

Ophthalmic Genet 2018 08 21;39(4):508-511. Epub 2018 May 21.

a Nuffield Laboratory of Ophthalmology & Oxford Biomedical Research Centre , University of Oxford , Oxford , UK.

Background: The growing number of clinical trials currently underway for inherited retinal diseases has highlighted the importance of achieving a molecular diagnosis for all new cases presenting to hospital eye services. The male germ cell-associated kinase (MAK) gene encodes a cilium-associated protein selectively expressed in the retina and testis, and has recently been implicated in autosomal recessive retinitis pigmentosa (RP). Whole exome sequencing has previously identified a homozygous Alu insertion in probands with recessive RP and nonsense and missense mutations have also been reported.

Materials And Methods: Here we describe two novel mutations in different alleles of the MAK gene in a 75-year-old British female, who had a clinical diagnosis of RP () with onset in the fourth decade and no relevant family history. The mutations were established through next generation sequencing of a panel of 111 genes associated with RP and RP-like phenotypes.

Results: Two novel null mutations were identified within the MAK gene. The first c.1195_1196delAC p.(Thr399fs), was a two base-pair deletion creating a frame-shift in exon 9 predicted to result in nonsense-mediated decay. The second, c.279-2A>G, involved the splice acceptor consensus site upstream of exon 4, predicted to lead to aberrant splicing.

Conclusions: The natural history of this individual's RP is consistent with previously described MAK mutations, being significantly milder than that associated with other photoreceptor ciliopathies. We suggest inclusion of MAK as part of wider genetic testing in all individuals presenting with RP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13816810.2018.1474369DOI Listing
August 2018

A splice-site variant in FLVCR1 produces retinitis pigmentosa without posterior column ataxia.

Ophthalmic Genet 2018 04 1;39(2):263-267. Epub 2017 Dec 1.

a Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences , Oxford University , Oxford, UK.

FLVCR1 (feline leukemia virus subgroup c receptor 1) is a transmembrane protein involved in the trafficking of intracellular heme. Homozygous variants in FLVCR1 have been described in association with a clinical syndrome of posterior column ataxia with retinitis pigmentosa (PCARP). Here, we describe a patient with non-syndromic retinitis pigmentosa homozygous for a splice-site variant in FLVCR1 (c.1092 + 5G>A) without evidence of posterior column ataxia or cerebellar degeneration. We suggest an association between intronic splice-site variants in FLVCR1 and the absence of posterior column degeneration and suggest a hypothesis to explain this observation. Should this association be proven, it would provide valuable prognostic information for patients. Retinal degeneration appears to be the sole clinical manifestation of this FLVCR1 variant; gene therapy approaches using an adeno-associated viral vector with sub-retinal delivery may therefore represent a therapeutic approach to halting retinal degeneration in this patient group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13816810.2017.1408848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841564PMC
April 2018

Two Novel CAPN5 Variants Associated with Mild and Severe Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy Phenotypes.

Ocul Immunol Inflamm 2019 17;27(5):693-698. Epub 2017 Oct 17.

a NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust , Oxford , United Kingdom.

: We report two new CAPN5 mutations associated with a phenotype of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy. : We performed next generation sequencing in two patients with ADNIV phenotype; the variants identified were explored further. : Patient 1 was heterozygous for CAPN5 c.799G>A, p.(Gly267Ser). Patient 2 was heterozygous for CAPN5 c.1126G>A, p.(Gly376Ser). Both amino acids are highly conserved across species. Patient 1 had a severe phenotype and his mutation lies within the protein's catalytic domain. Patient 2 had a mild phenotype and her mutation is the first ADNIV-causing mutation to be described in the regulatory domain of Calpain-5. : Our findings potentially add two new ADNIV-causing CAPN5 mutations to the three previously described. We recommend CAPN5 genetic testing in all patients with a possible ADNIV phenotype, to develop our understanding of Calpain-5; a protein which could potentially provide therapeutically accessible targets for the treatment of many leading causes of blindness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09273948.2017.1370651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711405PMC
January 2020

Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44.

Am J Hum Genet 2017 Sep;101(3):451-458

Nuffield Department of Clinical Neurosciences, University of Oxford, 6th Floor West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford OX3 7HE, UK. Electronic address:

The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591020PMC
September 2017

De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome.

Am J Hum Genet 2017 Jan 23;100(1):138-150. Epub 2016 Dec 23.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK; Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Windmill Road, Headington, Oxford OX3 7HE, UK. Electronic address:

Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study. The core phenotype includes moderate to severe intellectual disability, and many individuals exhibit cerebellar ataxia, subtle facial dysmorphism, strabismus, and vesicoureteric reflux, suggesting that EBF3 has a widespread developmental role. Pathogenic de novo variants identified in EBF3 include multiple loss-of-function and missense mutations. Structural modeling suggested that the missense mutations affect DNA binding. Functional analysis of mutant proteins with missense substitutions revealed reduced transcriptional activities and abilities to form heterodimers with wild-type EBF3. We conclude that EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223060PMC
January 2017

A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect.

Am J Hum Genet 2016 05 21;98(5):981-992. Epub 2016 Apr 21.

MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. Electronic address:

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863663PMC
May 2016

Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease.

Eur J Hum Genet 2013 Mar 12;21(3):274-80. Epub 2012 Sep 12.

Oxford Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Inherited retinal degeneration (IRD) is a common cause of visual impairment (prevalence ∼1/3500). There is considerable phenotype and genotype heterogeneity, making a specific diagnosis very difficult without molecular testing. We investigated targeted capture combined with next-generation sequencing using Nimblegen 12plex arrays and the Roche 454 sequencing platform to explore its potential for clinical diagnostics in two common types of IRD, retinitis pigmentosa and cone-rod dystrophy. 50 patients (36 unknowns and 14 positive controls) were screened, and pathogenic mutations were identified in 25% of patients in the unknown, with 53% in the early-onset cases. All patients with new mutations detected had an age of onset <21 years and 44% had a family history. Thirty-one percent of mutations detected were novel. A de novo mutation in rhodopsin was identified in one early-onset case without a family history. Bioinformatic pipelines were developed to identify likely pathogenic mutations and stringent criteria were used for assignment of pathogenicity. Analysis of sequencing metrics revealed significant variability in capture efficiency and depth of coverage. We conclude that targeted capture and next-generation sequencing are likely to be very useful in a diagnostic setting, but patients with earlier onset of disease are more likely to benefit from using this strategy. The mutation-detection rate suggests that many patients are likely to have mutations in novel genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2012.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573204PMC
March 2013

Fragile XE: an important differential diagnosis.

BMJ Case Rep 2010 23;2010. Epub 2010 Mar 23.

Dr Malathi Manipal Hospital, Paediatrics, Jayanagar 9th Block, Bangalore, 560078, India.

Fragile X is a common cause of mental retardation in boys that can also affect girls. We present the case of a 21-year-old woman with Fragile X E (FRAXE) with learning difficulty, behavioural problems and epilepsy. Her diagnosis was made after investigations spanning several years, highlighting the importance of considering FRAXE and the benefits of reviewing genetic test results in the light of advancing technology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr.06.2009.1964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027664PMC
October 2012

QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data.

Nucleic Acids Res 2007 6;35(6):2013-25. Epub 2007 Mar 6.

Genomics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford, UK.

Array-based technologies have been used to detect chromosomal copy number changes (aneuploidies) in the human genome. Recent studies identified numerous copy number variants (CNV) and some are common polymorphisms that may contribute to disease susceptibility. We developed, and experimentally validated, a novel computational framework (QuantiSNP) for detecting regions of copy number variation from BeadArray SNP genotyping data using an Objective Bayes Hidden-Markov Model (OB-HMM). Objective Bayes measures are used to set certain hyperparameters in the priors using a novel re-sampling framework to calibrate the model to a fixed Type I (false positive) error rate. Other parameters are set via maximum marginal likelihood to prior training data of known structure. QuantiSNP provides probabilistic quantification of state classifications and significantly improves the accuracy of segmental aneuploidy identification and mapping, relative to existing analytical tools (Beadstudio, Illumina), as demonstrated by validation of breakpoint boundaries. QuantiSNP identified both novel and validated CNVs. QuantiSNP was developed using BeadArray SNP data but it can be adapted to other platforms and we believe that the OB-HMM framework has widespread applicability in genomic research. In conclusion, QuantiSNP is a novel algorithm for high-resolution CNV/aneuploidy detection with application to clinical genetics, cancer and disease association studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkm076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874617PMC
May 2007