Publications by authors named "Sarah Hull"

66 Publications

Echocardiographic Assessment of the Aorta: Tips and Pitfalls.

Authors:
Sarah C Hull

Aorta (Stamford) 2020 Dec 24;8(6):161-162. Epub 2021 Mar 24.

Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut.

This Yale Aortic Institute lecture provides "tips and pitfalls" regarding echocardiographic assessment of the aorta.
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http://dx.doi.org/10.1055/s-0040-1721750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043812PMC
December 2020

3D Bioprinting using UNIversal Orthogonal Network (UNION) Bioinks.

Adv Funct Mater 2021 Feb 20;31(7). Epub 2020 Nov 20.

Department of Materials Science & Engineering, Stanford University, Stanford, CA 94305, USA.

Three-dimensional (3D) bioprinting is a promising technology to produce tissue-like structures, but a lack of diversity in bioinks is a major limitation. Ideally each cell type would be printed in its own customizable bioink. To fulfill this need for a universally applicable bioink strategy, we developed a versatile, bioorthogonal bioink crosslinking mechanism that is cell compatible and works with a range of polymers. We term this family of materials UNIversal, Orthogonal Network (UNION) bioinks. As demonstration of UNION bioink versatility, gelatin, hyaluronic acid (HA), recombinant elastin-like protein (ELP), and polyethylene glycol (PEG) were each used as backbone polymers to create inks with storage moduli spanning 200 to 10,000 Pa. Because UNION bioinks are crosslinked by a common chemistry, multiple materials can be printed together to form a unified, cohesive structure. This approach is compatible with any support bath that enables diffusion of UNION crosslinkers. Both matrix-adherent human corneal mesenchymal stromal cells and non-matrix-adherent human induced pluripotent stem cell-derived neural progenitor spheroids were printed with UNION bioinks. The cells retained high viability and expressed characteristic phenotypic markers after printing. Thus, UNION bioinks are a versatile strategy to expand the toolkit of customizable materials available for 3D bioprinting.
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http://dx.doi.org/10.1002/adfm.202007983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888563PMC
February 2021

Left ventricular myocardial strain and tissue characterization by cardiac magnetic resonance imaging in immune checkpoint inhibitor associated cardiotoxicity.

PLoS One 2021 19;16(2):e0246764. Epub 2021 Feb 19.

Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.

Background: Immune checkpoint inhibitors (ICIs) are highly effective in treating cancer; however, cardiotoxicity can occur, including myocarditis. Cardiac magnetic resonance (CMR) imaging is useful for evaluation of myocarditis, although it has not been well studied in ICI cardiotoxicity.

Methods: We identified patients referred for CMR evaluation of ICI cardiotoxicity from September 2015 through September 2019. We assessed structural and functional parameters, feature tracking (FT) left ventricular and atrial strain, T2- weighted ratios and quantitative late gadolinium enhancement (LGE). We also applied the Updated Lake Louise Criteria for diagnosis of myocarditis.

Results: Of the 20 patients referred, the median left ventricular ejection fraction (LVEF) was 52.5% ± 19.1 and 50% had a normal LVEF (≥53%). FT strain analysis revealed an average abnormal global longitudinal strain (GLS) of -9.8%± 4.2%. In patients with a normal LVEF, the average GLS remained depressed at -12.3%± 2.4%. In all patients, GLS demonstrated a significant negative correlation with LVEF (rs = -0.64, p 0.002). Sixteen patients (80%) had presence of LGE (14 non-ischemic pattern and 2 ischemic). Percent LGE did not correlate with any CMR parameters and notably did not correlate with LVEF (rs = -0.29, p = 0.22) or GLS (rs = 0.10, p = 0.67), highlighting the value of tissue characterization beyond functional assessment. Nine patients (45%) met full Updated Lake Louise Criteria and 85% met at least one criterion, suggestive of myocarditis in the correct clinical context. Thirteen patients (65%) were treated for ICI-associated myocarditis and, of these, 54% (n = 7) had recovery of LVEF to normal. There was no correlation between LVEF (p = 0.47), GLS (0.89), or % LGE (0.15) and recovery of LVEF with treatment.

Conclusion: In patients with suspected ICI cardiotoxicity, CMR is an important diagnostic tool, even in the absence of overt left ventricular dysfunction, as abnormalities in left ventricular strain, T2 signal and LGE can identifying disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246764PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895343PMC
February 2021

Triage and justice in an unjust pandemic: ethical allocation of scarce medical resources in the setting of racial and socioeconomic disparities.

J Med Ethics 2020 Oct 16. Epub 2020 Oct 16.

Solomon Center for Health Law & Policy, Yale Law School, New Haven, Connecticut, USA.

Shortages of life-saving medical resources caused by COVID-19 have prompted hospitals, healthcare systems, and governmentsto develop crisis standards of care, including 'triage protocols' to potentially ration medical supplies during the public health emergency. At the same time, the pandemic has highlighted and exacerbated racial, ethnic, and socioeconomic health disparities that together constitute a form of structural racism. These disparities pose a critical ethical challenge in developing fair triage systems that will maximize lives saved without perpetuating systemic inequities. Here we review alternatives to 'utilitarian' triage, including first-come first-served, egalitarian, and prioritarian systems of allocating scarce medical resources. We assess the comparative advantages and disadvantages of these allocation schemes. Ultimately, we argue that while triage protocols should not exacerbate disparities, they are not an adequate mechanism for redressing systemic health inequities. Entrenched health disparities must be addressed through broader social change.
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http://dx.doi.org/10.1136/medethics-2020-106457DOI Listing
October 2020

Developing a Triage Protocol for the COVID-19 Pandemic: Allocating Scarce Medical Resources in a Public Health Emergency.

J Clin Ethics 2020 ;31(4):303-317

Pediatrics and Program for Biomedical Ethics, Yale School of Medicine, in New Haven, Connecticut USA.

The coronavirus disease-2019 (COVID-19) has caused shortages of life-sustaining medical resources, and future waves of the virus may cause further scarcity. The Yale New Haven Health System developed a triage protocol to allocate scarce medical resources during the COVID-19 pandemic, with the primary goal of saving the most lives possible, and a secondary goal of making triage assessments and decisions consistent, transparent, and fair. We outline the process of developing the triage protocol, summarize the protocol itself, and discuss the major ethical challenges encountered, along with our answers to these challenges. These challenges include (1) the role of age and chronic comorbidities; (2) evaluating children and pregnant patients; (3) racial, ethnic, and socioeconomic disparities in health; (4) prioritization of healthcare workers; and (5) balancing clinical judgment versus protocolized assessments. We conclude with a review of the limitations of our protocol and the lessons learned. We hope that a robust public discussion of such protocols and the ethical challenges that they raise will result in the fairest possible processes, less need for triage, and more lives saved during future waves of the COVID-19 pandemic and similar public health emergencies.
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October 2020

Molecular and phenotypic investigation of a New Zealand cohort of childhood-onset retinal dystrophy.

Am J Med Genet C Semin Med Genet 2020 09 28;184(3):708-717. Epub 2020 Aug 28.

Department of Ophthalmology, University of Auckland, Auckland, New Zealand.

Inherited retinal diseases are clinically heterogeneous and are associated with nearly 300 different genes. In this retrospective, observational study of a consecutive cohort of 159 patients (134 families) with childhood-onset (<16 years of age) retinal dystrophy, molecular investigations, and in-depth phenotyping were performed to determine key clinical and molecular characteristics. The most common ocular phenotype was rod-cone dystrophy in 40 patients. Leber Congenital Amaurosis, the most severe form of retinal dystrophy, was present in 10 patients, and early onset severe retinal dystrophy in 22 patients. Analysis has so far identified 131 pathogenic or likely pathogenic variants including 22 novel variants. Molecular diagnosis was achieved in 112 of 134 families (83.6%) by NGS gene panel investigation in 60 families, Sanger sequencing in 27 families, and Asper microarray in 25 families. An additional nine variants of uncertain significance were also found including three novel variants. Variants in 36 genes have been identified with the most common being ABCA4 retinopathy in 36 families. Five sporadic retinal dystrophy patients were found to have variants in dominant and X-linked genes (CRX, RHO, RP2, and RPGR) resulting in more accurate genetic counseling of inheritance for these families. Variants in syndromic associated genes including ALMS1, SDCCAG8, and PPT1 were identified in eight families enabling directed systemic care.
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http://dx.doi.org/10.1002/ajmg.c.31836DOI Listing
September 2020

Scarce-Resource Allocation and Patient Triage During the COVID-19 Pandemic: JACC Review Topic of the Week.

J Am Coll Cardiol 2020 Jul 11;76(1):85-92. Epub 2020 May 11.

Department of Geriatrics and Palliative Medicine, VAPORHCS, Oregon Health Sciences University, Patient-Centered Education and Research, Portland, Oregon.

The COVID-19 pandemic and its sequelae have created scenarios of scarce medical resources, leading to the prospect that health care systems have faced or will face difficult decisions about triage, allocation, and reallocation. These decisions should be guided by ethical principles and values, should not be made before crisis standards have been declared by authorities, and, in most cases, will not be made by bedside clinicians. Do not attempt resuscitation and withholding and withdrawing decisions should be made according to standard determination of medical appropriateness and futility, but there are unique considerations during a pandemic. Transparent and clear communication is crucial, coupled with dedication to provide the best possible care to patients, including palliative care. As medical knowledge about COVID-19 grows, more will be known about prognostic factors that can guide these difficult decisions.
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http://dx.doi.org/10.1016/j.jacc.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213960PMC
July 2020

The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56.

Sci Rep 2020 Jan 28;10(1):1289. Epub 2020 Jan 28.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from different ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), five of which are novel including a deletion spanning the 5' untranslated region and the first coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identified in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the first MFRP genomic rearrangement, offering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.
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http://dx.doi.org/10.1038/s41598-019-57338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987234PMC
January 2020

Care Labor in VAD Therapy: Some Feminist Concerns.

Perspect Biol Med 2019 ;62(4):640-656

Ventricular assist device (VAD) care offers a distinctive lens through which we can explore unjust gender norms. This is a resource-intensive intervention, one in which increasingly sophisticated technology brings with it the need for more long-term care. This care work is demanding, involving device maintenance, medication and appointment management, household work, and emotional support. Most patients eligible for receiving VADs are men, so it is not surprising that it is more often women who are responsible for the care of patients with VADs. Still, there is room to question why so much of this labor is expected of and taken on by female caregivers, when it could be shared with male caregivers and even patients themselves. To the extent that gender difference in the distribution of this labor is avoidable and inequitable, it becomes in part a disparity resulting from unjust social norms. In order to unpack some of this injustice, the authors utilize empiric data and theoretical work in feminist ethics to articulate some of the mechanisms of the gender disparity in VAD care labor and to offer communitarian decision-making and redistribution of care labor as potential routes toward greater justice for women with respect to VAD therapy.
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http://dx.doi.org/10.1353/pbm.2019.0037DOI Listing
May 2020

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies.

Am J Ophthalmol 2020 02 5;210:59-70. Epub 2019 Nov 5.

Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; UK Inherited Retinal Dystrophy Consortium, United Kingdom. Electronic address:

Purpose: To describe the natural history of Leber congenital amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies.

Design: Retrospective case series.

Methods: Participants: Patients with GUCY2D-LCA at a single referral center.

Procedures: Review of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), electroretinography (ERG), and molecular genetic testing.

Main Outcome Measures: Demographic data, symptoms at presentation, visual acuity, evidence of progression, OCT and FAF findings, ERG assessment, and molecular genetics.

Results: Twenty-one subjects with GUCY2D-LCA were included, with a mean follow-up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-seven percent (n = 12) exhibited photophobia and 38% (n = 8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n = 15). Longitudinal assessment of VA showed stability in all patients, except 1 patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 of the 17 subjects (71%) with available refraction data. Eighteen subjects had either normal fundus appearance (n = 14) or a blond fundus (n = 3), while only 4 of the eldest subjects had mild retinal pigment epithelium (RPE) atrophy (mean, 49 years; range 40-54 years). OCT data were available for 11 subjects and 4 different grades of ellipsoid zone (EZ) integrity were identified: (1) continuous/intact EZ (n = 6), (2) focally disrupted EZ (n = 2), (3) focally disrupted with RPE changes (n = 2), and (4) diffuse EZ disruption with RPE changes (n = 1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients and undetectable ERGs in 1 subject. Novel genotype-phenotype correlations are also reported.

Conclusion: GUCY2D-LCA is a severe early-onset retinal dystrophy associated with very poor VA from birth. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity until late in the disease in the majority of subjects suggests a wide therapeutic window for gene therapy trials.
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http://dx.doi.org/10.1016/j.ajo.2019.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013380PMC
February 2020

Supplemental 25-Hydroxycholecalciferol Is More Effective than Cholecalciferol in Raising Serum 25-Hydroxyvitamin D Concentrations in Older Adults.

J Nutr 2020 01;150(1):73-81

DSM Nutritional Products Ltd., Human Nutrition and Health, Basel, Switzerland.

Background: There are few studies directly comparing the pharmacokinetics of 25-hydroxycholecalciferol [25(OH)D3] to cholecalciferol (D3).

Objectives: The primary objectives were to compare the effectiveness of D3 and 25(OH)D3 in raising 25-hydroxyvitamin D [25(OH)D] serum concentrations and achieving steady state.

Methods: This was a randomized, double-blind, active comparator trial of 91 participants (53 females, 38 males), aged 63.3 ± 7.9 y. 25(OH)D3 (10, 15, and 20 µg) and D3 (20 µg) were dosed daily for 6 mo followed by 6 mo of washout. Frequent measurements of serum 25(OH)D were performed. Pharmacokinetic parameters were fitted for each individual and the treatment average was modeled with linear regression using the individual baseline level, sex, and gender as covariates.

Results: Mean baseline 25(OH)D was similar in all groups (47.1-49.5 nmol/L). Increases in 25(OH)D to steady state were higher in the 25(OH)D3 groups than in the D3 group [least squares (LS) means (95% CI): 50.1 (43.3-58.0), 72.5 (64.3-81.7), 97.4 (86.6-109.6) nmol/L in 10, 15, and 20 µg/d and 38.7 (33.1-45.2) nmol/L in the D3 group; P = 0.0173, P < 0.0001, P < 0.0001]. The rate to reach steady state was similar in all groups, but the time to reach 25(OH)D concentrations of 75 nmol/L was faster in the higher-dosed 25(OH)D3 groups than in the D3 group (7 and 10 d compared with 40 d, P < 0.0001 and P < 0.0001 for 15 and 20 µg/d). The rate of elimination was 59-109% higher in the 25(OH)D3 groups than in the D3 group. The area under the curve (AUC)/µg dose demonstrated that 25(OH)D3 was 3 times as effective as D3 at raising 25(OH)D concentrations.

Conclusions: 25(OH)D3 is ∼3 times as effective as D3 at raising 25(OH)D concentrations. Once supplementation is discontinued, the elimination rate of 25(OH)D3 is faster than D3. This trial was registered at clinicaltrials.gov as NCT02333682.
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http://dx.doi.org/10.1093/jn/nxz209DOI Listing
January 2020

Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly.

Am J Ophthalmol 2019 11 8;207:87-98. Epub 2019 May 8.

UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom. Electronic address:

Purpose: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity.

Design: Retrospective case series.

Methods: Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).

Results: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and 2 missense variants were identified. Subsequent bone density measurement identified osteoporosis in one proband. Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 children with learning difficulties, abnormal peripheral retinal vasculogenesis, and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6. Three families remain unsolved following WES and WGS.

Conclusions: Molecular diagnosis has been achieved in 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.
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http://dx.doi.org/10.1016/j.ajo.2019.05.001DOI Listing
November 2019

Corneal Wound Healing Effects of Mesenchymal Stem Cell Secretome Delivered Within a Viscoelastic Gel Carrier.

Stem Cells Transl Med 2019 05 15;8(5):478-489. Epub 2019 Jan 15.

Department of Ophthalmology, Byers Eye Institute at Stanford University School of Medicine, Palo Alto, California, USA.

Severe corneal injuries often result in permanent vision loss and remain a clinical challenge. Human bone marrow-derived mesenchymal stem cells (MSCs) and their secreted factors (secretome) have been studied for their antiscarring, anti-inflammatory, and antiangiogeneic properties. We aimed to deliver lyophilized MSC secretome (MSC-S) within a viscoelastic gel composed of hyaluronic acid (HA) and chondroitin sulfate (CS) as a way to enhance corneal re-epithelialization and reduce complications after mechanical and chemical injuries of the cornea. We hypothesized that delivering MSC-S within HA/CS would have improved wound healing effects compared the with either MSC-S or HA/CS alone. The results showed that a once-daily application of MSC-S in HA/CS enhances epithelial cell proliferation and wound healing after injury to the cornea. It also reduced scar formation, neovascularization, and hemorrhage after alkaline corneal burns. We found that combining MSC-S and HA/CS increased the expression of CD44 receptors colocalized with HA, suggesting that the observed therapeutic effects between the MSC-S and HA/CS are in part mediated by CD44 receptor upregulation and activation by HA. The results from this study demonstrate a reproducible and efficient approach for delivering the MSC-S to the ocular surface for treatment of severe corneal injuries. Stem Cells Translational Medicine 2019;8:478-489.
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http://dx.doi.org/10.1002/sctm.18-0178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477005PMC
May 2019

Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.

PLoS Genet 2018 08 29;14(8):e1007504. Epub 2018 Aug 29.

Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.
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http://dx.doi.org/10.1371/journal.pgen.1007504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133373PMC
August 2018

Bio-Orthogonally Crosslinked, In Situ Forming Corneal Stromal Tissue Substitute.

Adv Healthc Mater 2018 10 14;7(19):e1800560. Epub 2018 Aug 14.

Byers Eye Institute at Stanford University School of Medicine, Palo Alto, CA, 94303, USA.

In this study, an in situ forming corneal stromal substitute based on collagen type I crosslinked by bio-orthogonal strain-promoted azide-alkyne cycloaddition (SPAAC) is presented. The crosslinked collagen gel has greater transparency compared to non-crosslinked collagen gels. The mechanical properties of the gels are controlled by changing functional group ratios and conjugated collagen concentrations. Higher concentrations of conjugated collagen yield enhances mechanical properties, where the storage modulus increases from 42.39 ± 8.95 to 112.03 ± 3.94 Pa after SPAAC crosslinking. Encapsulated corneal keratocytes grow within the SPAAC-crosslinked gels and corneal keratinocytes are supported on top of the gel surfaces. SPAAC-crosslinked gels support more favorable and stable keratinocyte morphology on their surface compared to non-crosslinked gels likely as a result of more optimal substrate stiffness, gel integrity, and resistance to degradation. SPAAC-crosslinked collagen gels with and without encapsulated keratocytes applied to rabbit corneas in an organ culture model after keratectomy exhibit surface epithelialization with multilayered morphology. The novel in situ forming gel is a promising candidate for lamellar and defect reconstruction of corneal stromal tissue.
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http://dx.doi.org/10.1002/adhm.201800560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417806PMC
October 2018

Tests for detecting strabismus in children aged 1 to 6 years in the community.

Cochrane Database Syst Rev 2017 11 6;11:CD011221. Epub 2017 Nov 6.

NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, 162 City Road, London, UK, EC1V 2PD.

Background: Strabismus (misalignment of the eyes) is a risk factor for impaired visual development both of visual acuity and of stereopsis. Detection of strabismus in the community by non-expert examiners may be performed using a number of different index tests that include direct measures of misalignment (corneal or fundus reflex tests), or indirect measures such as stereopsis and visual acuity. The reference test to detect strabismus by trained professionals is the cover‒uncover test.

Objectives: To assess and compare the accuracy of tests, alone or in combination, for detection of strabismus in children aged 1 to 6 years, in a community setting by non-expert screeners or primary care professionals to inform healthcare commissioners setting up childhood screening programmes.Secondary objectives were to investigate sources of heterogeneity of diagnostic accuracy.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library, the Health Technology Assessment Database (HTAD) in the Cochrane Library (2016, Issue 4), MEDLINE Ovid (1946 to 5 January 2017), Embase Ovid (1947 to 5 January 2017), CINAHL (January 1937 to 5 January 2017), Web of Science Conference Proceedings Citation Index-Science (CPCI-S) (January 1990 to 5 January 2017), BIOSIS Previews (January 1969 to 5 January 2017), MEDION (to 18 August 2014), the Aggressive Research Intelligence Facility database (ARIF) (to 5 January 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 5 January 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 5 January 2017 and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 5 January 2017. We did not use any date or language restrictions in the electronic searches for trials. In addition, orthoptic journals and conference proceedings without electronic listings were searched.

Selection Criteria: All prospective or retrospective population-based test accuracy studies of consecutive participants were included. Studies compared a single or combination of index tests with the reference test. Only those studies with sufficient data for analysis were included specifically to calculate sensitivity and specificity and determine diagnostic accuracy.Participants were aged 1 to 6 years. Studies reporting participants outside this range were included if subgroup data were available.Permitted settings included population-based vision screening programmes or opportunistic screening programmes, such as those performed in schools.

Data Collection And Analysis: We used standard methodological procedures expected by Cochrane. In brief, two review authors independently assessed titles and abstracts for eligibility and extracted the data, with a third senior author resolving any disagreement. We analysed data primarily for specificity and sensitivity.

Main Results: One study from a total of 1236 papers, abstracts and trials was eligible for inclusion with a total number of participants of 335 of which 271 completed both the screening test and the gold standard test. The screening test using an automated photoscreener had a sensitivity of 0.46 (95% confidence interval (CI) 0.19 to 0.75) and specificity of 0.97 (CI 0.94 to 0.99). The overall number affected by strabismus was low at 13 (4.8%).

Authors' Conclusions: There is very limited data in the literature to ascertain the accuracy of tests for detecting strabismus in the community as performed by non-expert screeners. A large prospective study to compare methods would be required to determine which tests have the greatest accuracy.
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http://dx.doi.org/10.1002/14651858.CD011221.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486041PMC
November 2017

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration.

JAMA Ophthalmol 2017 07;135(7):749-760

Casey Eye Institute, Oregon Health & Science University, Portland.

Importance: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported.

Objective: To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations.

Design, Setting, And Participants: A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years.

Main Outcomes And Measures: Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients.

Results: There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses.

Conclusions And Relevance: This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.
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http://dx.doi.org/10.1001/jamaophthalmol.2017.1401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710208PMC
July 2017

Missense mutations in the WD40 domain of cause non-syndromic retinitis pigmentosa.

J Med Genet 2017 09 25;54(9):624-632. Epub 2017 Apr 25.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Recent findings suggesting that () is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether variants cause non-syndromic retinitis pigmentosa (RP).

Methods: Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient's fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells.

Results: In the three patients with RP, three sets of compound heterozygous variants were detected in (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by , with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base.

Conclusions: This report confirms that mutations in can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated variants on protein function, thus proposing a new genotype-phenotype correlation for mutation associated retinal ciliopathies.
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http://dx.doi.org/10.1136/jmedgenet-2016-104200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574394PMC
September 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

Pleiotropic effect of a novel mutation in causing congenital cataract and a rare adult i blood group phenotype.

Hum Genome Var 2017 16;4:17004. Epub 2017 Feb 16.

UCL Institute of Ophthalmology , London, UK.

Mutations in have been associated with the rare adult i blood group phenotype with or without congenital cataract. We report a novel homozygous frameshift mutation c.1163_1166delATCA, p.(Asn388Argfs*20) as the cause of congenital cataract in two affected siblings. Blood group typing confirmed that both affected males have the rare adult i phenotype, supporting the hypothesis that the partial association of I/i phenotype and congenital cataract is due to the differential expression of isoforms.
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http://dx.doi.org/10.1038/hgv.2017.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311056PMC
February 2017

Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration.

Am J Hum Genet 2017 Feb 26;100(2):334-342. Epub 2017 Jan 26.

UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK. Electronic address:

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs63), c.1996C>T (p.Arg666), c.2632G>T (p.Glu878), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.
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http://dx.doi.org/10.1016/j.ajhg.2016.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294887PMC
February 2017

LVAD-DT: Culture of Rescue and Liminal Experience in the Treatment of Heart Failure.

Am J Bioeth 2017 Feb;17(2):3-11

f University of Washington Medical Center.

The purpose of this article is to investigate how cultural meanings associated with the left ventricular assist device (LVAD) inform acceptance and experience of this innovative technology when it is used as a destination therapy. We conducted open-ended, semistructured interviews with family caregivers and patients who had undergone LVAD-DT procedures at six U.S. hospitals. A grounded theory approach was used for the analysis. Thirty-nine patients and 42 caregivers participated. Participants described a sense of obligation to undergo the procedure because of its promise for salvation. However, once the device was implanted, patients described being placed into a liminal state of being neither sick nor healthy, with no culturally scripted role. Consideration of end-of-life decisions was complicated by the uncertainties about how patients with LVADs die. Pre-implantation communications among patient, family, and clinicians should take into account the impact of the technology on meaning, identity, and patient experience.
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http://dx.doi.org/10.1080/15265161.2016.1265162DOI Listing
February 2017

Clinical Characterization of CNGB1-Related Autosomal Recessive Retinitis Pigmentosa.

JAMA Ophthalmol 2017 Feb;135(2):137-144

Moorfields Eye Hospital, London, England2University College London Institute of Ophthalmology, London, England.

Importance: There are limited published data on the phenotype of retinitis pigmentosa (RP) related to CNGB1 variants. These data are needed both for prognostic counseling of patients and for understanding potential treatment windows.

Objective: To describe the detailed clinical and molecular genetic findings in a series of patients with RP with likely pathogenic variants in CNGB1.

Design, Setting, And Participants: In this case series, 10 patients from 9 families underwent full ophthalmologic examination. Molecular investigations included whole-exome analysis in 6 patients. The study was conducted from April 17, 2013, to March 3, 2016, with final follow-up completed on March 2, 2016, and data were analyzed from October 27, 2014, to March 29, 2016.

Main Outcomes And Measures: Results of ophthalmologic examination and molecular genetic analysis of CNGB1.

Results: In this case series, 7 women and 3 men from 9 families with a mean (SD) age of 47.4 (13.2) years identified as having CNGB1 variants were included in this study; there was a mean (SD) follow-up length of 3.7 (2.8) years. The first clinical presentation was with nyctalopia in childhood with visual field loss documented later at a mean (SD) age of 33.2 (8.0) years. All patients had preserved best-corrected visual acuity into adulthood, with a mean of 0.1 logMAR (Snellen equivalent, 20/25) in each eye (logMAR range, 0.0 to 0.3 [Snellen 20/20 to 20/40] in the right eye and -0.1 to 0.3 [Snellen 20/16 to 20/40] in the left eye). Fundus examination revealed midperipheral retinal pigment epithelial atrophy and intraretinal pigment migration. Optical coherence tomography of the macula demonstrated complete preservation of the inner segment ellipsoid band in 1 patient, with variable lateral extent in the other patients corresponding to the diameter of a paracentral ring of increased fundus autofluorescence. Electrophysiologic testing in 6 patients confirmed a rod-cone dystrophy phenotype. Molecular investigations identified a previously reported missense variant (p.[N986I]) and 7 variants not previously reported in disease including 4 nonsense (p.[(Q88*], p.[Q222*], p.[Q318*], and p.[R729*]), 2 frameshift (p.[A1048fs*13], p.[L849Afs*3]), and a splice site variant (c.761 + 2T>A).

Conclusions And Relevance: The data from this study suggest that visual acuity and foveal structure in patients with RP are preserved into adult life such that a lengthy window of opportunity should exist for intervention with novel therapies.
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http://dx.doi.org/10.1001/jamaophthalmol.2016.5213DOI Listing
February 2017

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Am J Hum Genet 2017 01 29;100(1):75-90. Epub 2016 Dec 29.

NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK.

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
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http://dx.doi.org/10.1016/j.ajhg.2016.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223092PMC
January 2017

Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.

Am J Hum Genet 2016 Dec 23;99(6):1305-1315. Epub 2016 Nov 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3411, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030-3411, USA. Electronic address:

Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.
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http://dx.doi.org/10.1016/j.ajhg.2016.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142109PMC
December 2016

Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa.

Invest Ophthalmol Vis Sci 2016 Nov;57(14):6180-6187

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 13Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, The Netherlands.

Purpose: AGBL5, encoding ATP/GTP binding protein-like 5, was previously proposed as an autosomal recessive retinitis pigmentosa (arRP) candidate gene based on the identification of missense variants in two families. In this study, we performed next-generation sequencing to reveal additional RP cases with AGBL5 variants, including protein-truncating variants.

Methods: Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in three probands. Subsequent Sanger sequencing and segregation analysis were performed in the selected candidate genes. The medical history of individuals carrying AGBL5 variants was reviewed and additional ophthalmic examinations were performed, including fundus photography, fundus autofluorescence imaging, and optical coherence tomography.

Results: AGBL5 variants were identified in three unrelated arRP families, comprising homozygous variants in family 1 (c.1775G>A:p.(Trp592*)) and family 2 (complex allele: c.[323C>G; 2659T>C]; p.[(Pro108Arg; *887Argext*1)]), and compound heterozygous variants (c.752T>G:p.(Val251Gly) and c.1504dupG:p.(Ala502Glyfs*15)) in family 3. All affected individuals displayed typical RP phenotypes.

Conclusions: Our study convincingly shows that variants in AGBL5 are associated with arRP. The identification of AGBL5 and TTLL5, a previously described RP-associated gene encoding the tubulin tyrosine ligase-like family, member 5 protein, highlights the importance of poly- and deglutamylation in retinal homeostasis. Further studies are required to investigate the underlying disease mechanism associated with AGBL5 variants.
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http://dx.doi.org/10.1167/iovs.16-20148DOI Listing
November 2016

Reevaluation of the Retinal Dystrophy Due to Recessive Alleles of RGR With the Discovery of a Cis-Acting Mutation in CDHR1.

Invest Ophthalmol Vis Sci 2016 09;57(11):4806-13

UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.

Purpose: Mutation of RGR, encoding retinal G-protein coupled receptor was originally reported in association with retinal dystrophy in 1999. A single convincing recessive variant segregated perfectly in one family of five affected and two unaffected siblings. At least one further individual, homozygous for the same variant has since been reported. The aim of this report was to reevaluate the findings in consideration of data from a whole genome sequencing (WGS) study of a large cohort of retinal dystrophy families.

Methods: Whole genome sequencing was performed on 599 unrelated probands with inherited retinal disease. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging (FAF) and spectral-domain optical coherence tomography (OCT).

Results: Overall we confirmed that affected individuals from six unrelated families were homozygous for both the reported RGR p.Ser66Arg variant and a nearby frameshifting deletion in CDHR1 (p.Ile841Serfs119*). All had generalized rod and cone dysfunction with severe macular involvement. An additional proband was heterozygous for the same CDHR1/RGR haplotype but also carried a second null CDHR1 mutation on a different haplotype. A comparison of the clinical presentation of the probands reported here with other CDHR1-related retinopathy patients shows the phenotypes to be similar in presentation, severity, and rod/cone involvement.

Conclusions: These data suggest that the recessive retinal disorder previously reported to be due to homozygous mutation in RGR is, at least in part, due to variants in CDHR1 and that the true consequences of RGR knock-out on human retinal structure and function are yet to be determined.
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http://dx.doi.org/10.1167/iovs.16-19687DOI Listing
September 2016

Expanding the Phenotype of TRNT1-Related Immunodeficiency to Include Childhood Cataract and Inner Retinal Dysfunction.

JAMA Ophthalmol 2016 Sep;134(9):1049-53

Institute of Ophthalmology, University College London, London, England2Moorfields Eye Hospital, London, England7Department of Ophthalmology, University of California, San Francisco.

Importance: A multiorgan syndromic disorder characterized by sideroblastic anemia, immunodeficiency, periodic fever, and developmental delay with an uncharacterized retinal dystrophy is caused by TRNT1. This report of a family with a homozygous mutation in TRNT1 expands the ocular phenotype to include cataract and inner retinal dysfunction and details a mild systemic phenotype.

Observations: A consanguineous family with 3 affected children was investigated. Key clinical features comprised hypogammaglobulinemia, short stature with microcephaly, cataract, and inner retinal dysfunction without sideroblastic anemia or developmental delay. Two siblings had poor balance and 1 sibling had sensorineural hearing loss. The oldest sibling had primary ovarian failure diagnosed at age 14.5 years. Exome sequencing identified a homozygous missense variant in TRNT1, c.295C>T (p.Arg99Trp) in all 3 patients. The sibling with hearing loss also harbored a homozygous mutation in GJB2, c.71G>A (p.Trp24*), which is an established cause of sensorineural hearing loss.

Conclusions And Relevance: This family expands the ocular and systemic phenotypes associated with mutations in TRNT1, demonstrating phenotypic variability and highlighting the need for ophthalmic review of these patients.
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http://dx.doi.org/10.1001/jamaophthalmol.2015.5833DOI Listing
September 2016