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    The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort
    (Wiley, 2020-05) Siggs, Owen M; Awadalla, Mona S; Souzeau, Emmanuelle; Staffieri, Sandra E; Kearns, Lisa A; Laurie, Kate; Kuot, Abraham; Qassim, Ayub; Edwards, Thomas L; Coote, Michael A; Mancel, Erica; Walland, Mark J; Dondey, Joanne; Galanopoulous, Anna; Casson, Robert J; Mills, Richard A; MacArthur, Daniel G; Ruddle, Jonathan B; Burdon, Kathryn P; Craig, Jamie E
    Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF , TMEM98 , MFRP , and PRSS56 . Two of four PRSS56 families harbored the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.
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    An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity
    (Elsevier, 2020-01) Qassim, Ayub; Souzeau, Emmanuelle; Siggs, Owen M; Hassall, Mark M; Han, Xikun; Griffiths, Helen L; Frost, N Andrew; Vallabh, Neeru A; Kirwan, James F; Menon, Geeta; Cree, Angela J; Galanopoulos, Anna; Agar, Ashish; Healey, Paul R; Graham, Stuart L; Landers, John; Casson, Robert J; Gharahkhani, Puya; Willoughby, Colin E; Hewitt, Alex W; Lotery, Andrew J; MacGregor, Stuart; Craig, Jamie E
    Purpose To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. Design Cross-sectional study. Participants For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. Methods Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. Main Outcome Measures Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. Results A dose–response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1–2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). Conclusions The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.
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    Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma
    (Elsevier, 2020-01) Siggs, Owen M; Souzeau, Emmanuelle; Taranath, Deepa A; Dubowsky, Andrew; Chappell, Angela; Zhou, Tiger; Javadiyan, Shari; Nicholl, Jillian; Kearns, Lisa A; Staffieri, Sandra E; Narita, Andrew; Ruddle, Jonathan B; Elder, James E; Mackey, David A; Burdon, Kathryn P; Craig, Jamie E
    Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective, multicenter case series. Participants A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency < 4×10−5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest–derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment.
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    Intraocular Chemotherapy for Vitreoretinal Lymphoma: a review
    (Wiley, 2019-11-03) Kvopka, Michael; Lake, Stewart; Smith, Justine R
    Vitreoretinal lymphomas are rare ocular cancers, and the subset of primary central nervous system lymphomas that are based in the posterior eye. These tumours are challenging to treat, and today management generally involves a multispecialty team coordinating a treatment protocol that may include intraocular chemotherapy, ocular irradiation, systemic chemotherapy and/or autologous stem cell transplantation. The ophthalmologist has specific responsibility for the intraocular chemotherapy, which is delivered to the eye by intravitreal injection. The most commonly injected drugs are methotrexate—an anti‐metabolite—and rituximab—an anti‐human B cell monoclonal antibody. A range of intraocular chemotherapy treatment schedules have been described in the medical literature, although to date there have been no randomized clinical trials of these schedules. In this article, we review the development and current status of intraocular chemotherapy for vitreoretinal lymphoma.
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    Primary congenital glaucoma due to paternal uniparental isodisomy of chromosome 2 and CYP1B1 deletion
    (Wiley, 2019-08-01) Souzeau, Emmanuelle; Dubowsky, Andrew; Ruddle, Jonathan B; Craig, Jamie E
    Background: CYP1B1 variants and deletions are the most common cause of primary congenital glaucoma (PCG). Methods: We investigated an individual with PCG from the Australian and New Zealand Registry of Advanced Glaucoma. We performed sequencing of the CYP1B1 gene, followed by Multiplex Ligation-dependent Probe Amplification and SNP array. Results: We identified a homozygous deletion of the CYP1B1 gene by Multiplex Ligation-dependent Probe Amplification and confirmed that the father was heterozygous for a CYP1B1 deletion but the mother had normal gene copy number. SNP array identified paternal uniparental isodisomy of the entire chromosome 2. Conclusions: This study is the first report of a homozygous CYP1B1 whole gene deletion due to paternal uniparental isodisomy of chromosome 2 as a cause of PCG. These results illustrate the importance of genetic testing in providing appropriate genetic counseling regarding the risks of recurrence.
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    Autosomal dominant nanophthalmos and high hyperopia associated with a C-terminal frameshift variant in MYRF
    (Molecular Vision, 2019-09-21) Siggs, Owen M; Souzeau, Emmanuelle; Breen, James; Qassim, Ayub; Zhou, Tiger; Dubowsky, Andrew; Ruddle, Jonathan B; Craig, Jamie E
    Purpose: Nanophthalmos is a rare subtype of microphthalmia associated with high hyperopia and an increased risk of angle-closure glaucoma. We investigated the genetic cause of nanophthalmos and high hyperopia in an autosomal dominant kindred. Methods: A proband with short axial length, high hyperopia, and dextrocardia was subjected to exome sequencing. Human and rodent gene expression data sets were used to investigate the expression of relevant genes. Results: We identified a segregating heterozygous frameshift variant at the 3′ end of the penultimate exon of MYRF. Using Myc-MYRF chromatin immunoprecipitation data from rat oligodendrocytes, MYRF was found to bind immediately upstream of the transcriptional start site of Tmem98, a gene that itself has been implicated in autosomal dominant nanophthalmos. MYRF and TMEM98 were found to be expressed in the human retina, with a similar pattern of expression across several dissected human eye tissues. Conclusions: C-terminal variants in MYRF, which are expected to escape nonsense-mediated decay, represent a rare cause of autosomal dominant nanophthalmos with or without dextrocardia or congenital diaphragmatic hernia.
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    Intracameral antibiotics for prophylaxis of post operative endophthalmitis in Australia : comment
    (Wiley, 2019-10-01) Phillips, Cameron J; Mills, Richard Arthur
    We read with interest the article by Lipsky and Barrett and concur that intracameral moxifloxacin is a safer and more efficacy alternative to vancomycin as evidence emerges of postoperative haemorrhagic occlusive retinal vasculitis (HORV) associated with vancomycin.1 However we wish to redress the point stated about lack of avilability in Australia. Moxifloxacin is available in Australia for preparation into intracameral formulation. In our centre, when managing patients with penicillin or β-lactam allergy, we have ceased using vancomycin and now routinely administer intracameral moxifloxacin. We report the steps undertaken to implement this change in our care pathway.
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    The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results
    (Elsevier, 2019-04-04) Bombard, Yvonne; Brothers, Kyle B; Fitzgerald-Butt, Sara; Garrison, Nanibaa' A; Jamal, Leila; James, Cynthia A; Jarvik, Gail P; McCormick, Jennifer B; Nelson, Tanya N; Ormond, Kelly E; Rehm, Heidi L; Richer, Julie; Souzeau, Emmanuelle; Vassy, Jason L; Wagner, Jennifer K; Levy, Howard P
    The evidence base supporting genetic and genomic sequence-variant interpretations is continuously evolving. An inherent consequence is that a variant’s clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis. There has been discussion concerning the extent of this obligation in the context of both research and clinical care. Although clinical recommendations have begun to emerge, guidance is lacking on the responsibilities of researchers to inform participants of reinterpreted results. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in November 2018. The workgroup included representatives from the National Society of Genetic Counselors, the Canadian College of Medical Genetics, and the Canadian Association of Genetic Counsellors. The final statement includes twelve position statements that were endorsed or supported by the following organizations: Genetic Alliance, European Society of Human Genetics, Canadian Association of Genetic Counsellors, American Association of Anthropological Genetics, Executive Committee of the American Association of Physical Anthropologists, Canadian College of Medical Genetics, Human Genetics Society of Australasia, and National Society of Genetic Counselors.
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    Rare, potentially pathogenic variants in 21 keratoconus candidate genes are not enriched in cases in a large Australian cohort of European descent
    (Public LIbrary of Science, 2018-06-20) Lucas, Sionne E; Zhou, Tiger; Blackburn, Nicholas B; Mills, Richard Arthur; Ellis, Jonathan; Leo, Paul; Souzeau, Emmanuelle; Ridge, Bronwyn; Charlesworth, Jac C; Lindsay, Richard; Craig, Jamie E; Burdon, Kathryn Penelope
    Many genes have been suggested as candidate genes for keratoconus based on their function, their proximity to associated polymorphisms or due to the identification of putative causative variants within the gene. However, very few of these genes have been assessed for rare variation in keratoconus more broadly. In contrast, VSX1 and SOD1 have been widely assessed, however, the vast majority of studies have been small and the findings conflicting. In a cohort of Australians of European descent, consisting of 385 keratoconus cases and 396 controls, we screened 21 keratoconus candidate genes: BANP, CAST, COL4A3, COL4A4, COL5A1, FOXO1, FNDC3B, HGF, IL1A, IL1B, ILRN, IMMP2L, MPDZ, NFIB, RAB3GAP1, RAD51, RXRA, SLC4A11, SOD1, TF and VSX1. The candidate genes were sequenced in these individuals by either whole exome sequencing or targeted gene sequencing. Variants were filtered to identify rare (minor allele frequency <1%), potentially pathogenic variants. A total of 164 such variants were identified across the two groups with no variants fulfilling these criteria in cases in IL1RN, BANP, IL1B, RAD51 or SOD1. The frequency of variants was compared between cases and controls using chi-square or Fishers’ Exact tests for each gene with at least one rare potentially pathogenic variant identified in the case cohort. The number of rare potentially pathogenic variants per gene ranged from three (RXRA) to 102 (MPDZ), however for all genes, there was no difference in the frequency between the cases and controls. We conclude that rare potentially pathogenic variation in the 21 candidate genes assessed do not play a major role in keratoconus susceptibility and pathogenesis.
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    Influence of the time of day on axial length and choroidal thickness changes to hyperopic and myopic defocus in human eyes
    (Elsevier, 2019-03-26) Moderiano, Daniel; Do, Michelle; Hobbs, Sam; Lam, Vy; Sarin, Simran; Alonso-Caneiro, David A; Chakraborty, Ranjay
    Research in animal models have shown that exposing the eye to positive or negative spectacle lenses can lead to predictable changes in eye growth. Recent research indicates that brief periods (1–2 h) of monocular defocus results in small, but significant changes in axial length and choroidal thickness of human subjects. However, the effects of the time of day on these ocular changes with defocus are not known. In this study, we examined the effects of monocular myopic and hyperopic defocus on axial length and choroidal thickness when applied in the morning (change between 10 a.m. and 12 p.m.) vs the evening (change between 5 and 7 p.m.) in young adult human participants (mean age, 23.44 ± 4.52 years). A series of axial length (using an IOL Master) and choroidal thickness (using an optical coherence tomographer) measurements were obtained over three consecutive days in both eyes. Day 1 (no defocus) examined the baseline ocular measurements in the morning (10 a.m. and 12 p.m.) and in the evening (5 and 7 p.m.), day 2 investigated the effects of hyperopic and myopic defocus on ocular parameters in the morning (subjects wore a spectacle lens with +3 or −3 DS over the right eye and a plano lens over the left eye between 10 a.m. and 12 p.m.), and day 3 examined the effects of defocus in the evening (+3 or −3 DS spectacle lens over the right eye between 5 and 7 p.m.). Exposure to myopic defocus caused a significant reduction in axial length and thickening of the subfoveal choroid at both times; but, compared to baseline data from day 1, the relative change in axial length (−0.021 ± 0.009 vs +0.004 ± 0.003 mm, p = 0.009) and choroidal thickness (+0.027 ± 0.006 vs +0.007 ± 0.006 mm, p = 0.011) with defocus were significantly greater for evening exposure to defocus than for the morning session. On the contrary, introduction of hyperopic defocus resulted in a significant increase in axial length when given in the morning (+0.026 ± 0.006 mm), but not in the evening (+0.001 ± 0.003 mm) (p = 0.047). Furthermore, hyperopic defocus resulted in a significant thinning of the choroid (p = 0.005), but there was no significant influence of the time of day on choroidal changes associated with hyperopic defocus (p = 0.672). Exposure to hyperopic and myopic defocus at different times of the day was also associated with changes in the parafoveal regions of the choroid (measured across 1.5 mm nasal and temporal choroidal regions on either side of the fovea). Our results show that ocular response to optical defocus varies significantly depending on the time of day in human subjects. These findings represent a potential interaction between the signal associated with the eye's natural diurnal rhythm and the visual signal associated with the optical defocus, making the eye perhaps more responsive to hyperopic defocus (or ‘go’ signal) in the morning, and to myopic defocus (or ‘stop’ signal) in the latter half of the day.
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    Macular GCIPL loss precedes peripapillary RNFL loss in glaucoma with lower intraocular pressure
    (Elsevier, 2019-03-22) Marshall, Henry; Andrew, Nicholas H; Hassall, Mark; Qassim, Ayub; Souzeau, Emmanuelle; Ridge, Bronwyn; Nguyen, Thi; Fitzgerald, Jude T; Awadalla, Mona S; Burdon, Kathryn Penelope; Healey, Paul R; Agar, Ashish; Galanopoulos, Anna; Hewitt, Alex W; Graham, Stuart L; Landers, John; Casson, Robert J; Craig, Jamie E
    Purpose To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fibre layer (pRNFL) or macular ganglion cell-inner plexiform layer (mGCIPL). Design Prospective longitudinal cohort study. Participants 271 eyes from 207 individuals with statistically significant evidence of glaucomatous progression on optical coherence tomography (OCT)-Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance. Methods Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared to individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis. Outcome Measures Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL. Results IOP, baseline pRNFL thickness, baseline mGCIPL thickness and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pre-treatment IOP (mean difference: 3.90mmHg, 95%CI: 2.37-5.43; p<0.001). The time interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5mmHg increase in IOP (95%CI: 10.32 -15.72). Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference: 7.07μm; 95%CI: 4-38-9.77; p<0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to develop a new paracentral field defect than cases progressing first on pRNFL parameters (OR: 3.03; 95%CI: 1.26-7.28; p=0.01). Conclusion Clinical features, particularly pre-treatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the utility of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.
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    Genetic polymorphism of the methotrexate transporter ABCG2, blood pressure and markers of arterial function in patients with rheumatoid arthritis: repeated cross-sectional study
    (Dove Press, 2018-11-12) Baghdadi, Leena R; Woodman, Richard John; Shanahan, Ernst Michael; Wiese, Michael D; Mangoni, Arduino Aleksander
    Purpose: Methotrexate (MTX) treatment is associated with lower blood pressure (BP) and arterial stiffness in rheumatoid arthritis (RA). We investigated associations between single-nucleotide polymorphism (SNP) of the ATP-binding cassette efflux transporter gene ABCG2 (rs2231142), BP, and arterial stiffness in RA patients treated with MTX. Patients and methods: Clinical and 24-hour peripheral and central BP, arterial wave reflection (Augmentation Index, AIx), arterial stiffness (Pulse Wave Velocity, PWV), and intracellular MTX polyglutamate (MTXPGs) concentrations were assessed in 56 RA patients on stable treatment with MTX using a repeated cross-sectional study design with measurements at baseline and after 8 months. Results: Majority of the RA patients were homozygotes for the normal allele (CC, n=46) whereas 10 were rs2231142 heterozygotes (AC, n=10). MTXPGs concentrations were non-significantly higher in AC when compared to CC (144.3 vs 116.3 nmol/L packed RBCs, P=0.10). At baseline, the AC group had significantly lower age-adjusted clinical systolic BP (SBP) (P=0.01), 24-hour peripheral SBP (P=0.003), and central SBP (P=0.02) when compared to the CC group. However, AIx and PWV values were not significantly different between the two groups. When data from both visits were combined in a single analysis, and additionally adjusted for visit, gender, body mass index, and Disease Activity Score 28, the trend in SBP differences between-groups persisted but was no longer significant. Conclusion: Future studies are required to test the hypothesis that this genetic polymorphism is associated with lower BP, arterial stiffness, and possibly, cardiovascular risk, in RA patients treated with MTX.
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    Prevalence and type of artefact with spectral domain optical coherence tomography macular ganglion cell imaging in glaucoma surveillance
    (Public Library of Science, 2018-12-05) Awadalla, Mona S; Fitzgerald, Jude T; Andrew, Nicholas H; Zhou, Tiger; Marshall, Henry; Qassim, Ayub; Hassall, Mark; Casson, Robert J; Graham, Stuart L; Healey, Paul R; Agar, Ashish; Galanopoulos, Anna; Phipps, Simon; Chappell, Angela J; Landers, John; Craig, Jamie E
    Purpose The ganglion cell analysis (GCA) of the CIRRUSTM HD-OCT (Carl Zeiss, Meditec; Dublin, CA) provides measurement of the macular ganglion cell-inner plexiform layer (GCIPL) thickness. This study determined the frequency of scan artefacts and errors in GCIPL imaging in individuals undergoing HD-OCT surveillance for glaucoma. Method A total of 1439 eyes from 721 subjects enrolled in a prospective study assessing predictors of glaucoma progression underwent macular GCIPL imaging with the CIRRUS HD-OCT at recruitment. The prevalence of acquisition errors, segmentation errors, and co-morbid macular pathology was determined. Results A total of 87 (6.0%) of the 1439 scans had either acquisition errors, segmentation artefacts, or other macular pathology. The most common co-morbid macular pathology was epiretinal membrane in 2.2% of eyes. Conclusion The macular GCIPL scan was artefact free in 94% of eyes. However, epiretinal membrane and high myopia can cause scan artefact and should be considered when interpreting the results.
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    Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
    (Springer Nature, 2018-05-14) Iglesias, Adriana; Mishra, Aniket; Vitart, Veronique; Bykhovskaya, Yelena; Hohn, Rene; Springelkamp, Henriet; Cuellar-Partida, Gabriel; Gharahkhani, Puya; Cooke Bailey, Jessica N; Willoughby, Colin E; Li, Xiaohui; Yazar, Seyhan; Nag, Abhishek; Khawaja, Anthony; Polasek, Ozren; Siscovick, David; Mitchell, Paul; Tham, Yih Chung; Haines, Jonathan L; Kearns, Lisa S; Hayward, Caroline; Shi, Yan; van Leeuwen, Elisabeth M; Taylor, Kent D; Blue Mountains Eye Study - GWAS group,; Bonnemaijer, Pieter; Rotter, Jerome I; Martin, Nicholas G; Zeller, Tanja; Mills, Richard Arthur; Souzeau, Emmanuelle; Staffieri, Sandra E; Jonas, Jost B; Schmidtmann, Irene; Boutin, Thibaud; Kang, Jae Hee; Lucas, Sionne E; Wong, Tien Yin; Beutel, Manfred E; Wilson, James F; Neighborhood Consortium; Uitterlinden, Andre G; Vithana, Eranga; Foster, Paul J; Hysi, Pirro G; Hewitt, Alex W; Khor, Chiea Chuen; Pasquale, Louis R; Montgomery, Grant W; Klaver, Caroline C W; Aung, Tin; Pfeiffer, Norbert; Mackey, David A; Hammond, Christopher J; Cheng, Ching-Yu; Craig, Jamie E; Rabinowitz, Yaron S; Wiggs, Janey L; van Duijn, Cornelia M; MacGregor, Stuart
    Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
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    Prevalence of FOXC1 Variants in Individuals With a Suspected Diagnosis of Primary Congenital Glaucoma
    (American Medical Association, 2019-01-17) Siggs, Owen M; Souzeau, Emmanuelle; Pasutto, Francesca; Dubowsky, Andrew; Smith, James E H; Taranath, Deepa A; Pater, John Brian; Rait, Julian L; Narita, Andrew; Mauri, Lucia; Del Longo, Alessandra; Reis, Andre; Chappell, Angela J; Kearns, Lisa A; Staffieri, Sandra E; Elder, James E; Ruddle, Jonathan B; Hewitt, Alex W; Burdon, Kathryn Penelope; Mackey, David A; Craig, Jamie E
    Importance Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma. Objective To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma. Design, Setting, and Participants Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l’Azienda Socio–Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017. Main Outcome and Measures Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them. Results A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome. Conclusions and Relevance These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.
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    Lack of cone mediated retinal function increases susceptibility to form-deprivation myopia in mice
    (Elsevier, 2018-12-31) Chakraborty, Ranjay; Yang, Victoria; Park, Han Na; Landis, Erica G; Dhakal, Susov; Motz, Cara T; Bergen, Michael A; Iuvone, P Michael; Pardue, Machelle T
    Retinal photoreceptors are important in visual signaling for normal eye growth in animals. We used Gnat2cplf3/cplf3 (Gnat2−/−) mice, a genetic mouse model of cone dysfunction to investigate the influence of cone signaling in ocular refractive development and myopia susceptibility in mice. Refractive development under normal visual conditions was measured for Gnat2−/− and age-matched Gnat2+/+ mice, every 2 weeks from 4 to 14 weeks of age. Weekly measurements were performed on a separate cohort of mice that underwent monocular form-deprivation (FD) in the right eye from 4 weeks of age using head-mounted diffusers. Refraction, corneal curvature, and ocular biometrics were obtained using photorefraction, keratometry and optical coherence tomography, respectively. Retinas from FD mice were harvested, and analyzed for dopamine (DA) and 3,4-dihydroxyphenylacetate (DOPAC) using high-performance liquid chromatography. Under normal visual conditions, Gnat2+/+ and Gnat2−/− mice showed similar refractive error, axial length, and corneal radii across development (p > 0.05), indicating no significant effects of the Gnat2 mutation on normal ocular refractive development in mice. Three weeks of FD produced a significantly greater myopic shift in Gnat2−/− mice compared to Gnat2+/+ controls (−5.40 ± 1.33 D vs −2.28 ± 0.28 D, p = 0.042). Neither the Gnat2 mutation nor FD altered retinal levels of DA or DOPAC. Our results indicate that cone pathways needed for high acuity vision in primates are not as critical for normal refractive development in mice, and that both rods and cones contribute to visual signalling pathways needed to respond to FD in mammalian eyes. Note: Aspects of the article have been presented at the American Academy of Optometry meeting on November 2016 in Anaheim, California, USA.
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    Loss of ciliary zonule protein hydroxylation and lens stability as a predicted consequence of biallelic ASPH variation
    (Taylor & Francis Group, 2019-01-02) Siggs, Owen M; Souzeau, Emmanuelle; Craig, Jamie E
    Purpose: Stability of the crystalline lens requires formation of microfibril bundles and their higher-order structures of ciliary zonules. Trauma, malformation, or degeneration of the ciliary zonules can lead to dislocation or displacement of the lens, which in turn can cause transient or permanent loss of visual acuity. The purpose of this study was to identify the predicted substrates of ASPH, a 2-oxoglutarate- and Fe2+-dependent hydroxylase, which may account for the lens instability phenotype of ASPH-associated syndromes. Methods: A single proband of European ancestry with spherophakia and high myopia was subjected to exome sequencing. Proteins containing the ASPH hydroxylation motif were identified within the SwissProt protein database. Results: We identified 105 putative substrates of ASPH-mediated hydroxylation in the human proteome, of which two (FBN1 and LTBP2) are associated with inherited ectopia lentis syndromes, and are essential for microfibril and ciliary zonule development. Conclusion: Our results implicate ASPH-mediated hydroxylation in the formation of FBN1/LTBP2 microfibril bundles and competent ciliary zonules.
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    Maternal uniparental isodisomy of chromosome 6 unmasks a novel variant in TULP1 in a patient with early onset retinal dystrophy
    (Molecular Vision, 2018-07-21) Souzeau, Emmanuelle; Thompson, Jennifer A; McLaren, Terri L; De Roach, John N; Barnett, Christopher P; Lamey, Tina M; Craig, Jamie E
    Purpose Inherited retinal dystrophies are a clinically and genetically heterogeneous group of disorders. Molecular diagnosis has proven utility for affected individuals. In this study, we report an individual enrolled in the Australian Inherited Retinal Disease Registry and DNA Bank diagnosed with clinical features overlapping between Leber congenital amaurosis and retinitis pigmentosa. Methods DNA from the proband was sequenced using a gene panel for inherited retinal disorders, and a single nucleotide polymorphism (SNP) array was conducted to detect the presence of deletions and uniparental disomy. Results We identified a novel homozygous variant (c.524dupC, p.(Pro176ThrfsTer7)) in TULP1 resulting from maternal uniparental isodisomy of chromosome 6. The patient had clinical features consistent with biallelic pathogenic variants in TULP1, including congenital nystagmus, night blindness, non-recordable electroretinogram, mild myopia, and mild peripheral pigmentary changes in the fundus. Conclusions This is the first report of uniparental disomy 6 and a homozygous variant in TULP1 associated with a rod-cone dystrophy. Molecular diagnosis of inherited retinal dystrophies is essential to inform the mode of transmission and clinical management, and to identify potential candidates for future gene-specific therapies.
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    Identification of novel mutations causing pediatric cataract in Bhutan, Cambodia, and Sri Lanka
    (Wiley, 2018-04-05) Javadiyan, Shahrbanou; Lucas, Sionne E; Wangmo, Dechen; Ngy, Meng; Edussuriya, Kapila; Craig, Jamie E; Rudkin, Adam K; Casson, Robert J; Selva, Dinesh; Sharma, Shiwani; Lower, Karen Marie; Meucke, James; Burdon, Kathryn Penelope
    Background: Pediatric cataract is an important cause of blindness and visual impairment in children. A large proportion of pediatric cataracts are inherited, and many genes have been described for this heterogeneous Mendelian disease. Surveys of schools for the blind in Bhutan, Cambodia, and Sri Lanka have identified many children with this condition and we aimed to identify the genetic causes of inherited cataract in these populations. Methods: We screened, in parallel, 51 causative genes for inherited cataracts in 33 probands by Ampliseq enrichment and sequencing on an Ion Torrent PGM. Rare novel protein coding variants were assessed for segregation in family members, where possible, by Sanger sequencing. Results: We identified 24 rare (frequency <1% in public databases) or novel protein coding variants in 12 probands and confirmed segregation of variants with disease in the extended family where possible. Of these, six are predicted to be the cause of disease in the patient, with four other variants also highly likely to be pathogenic. Conclusion: This study found that 20%–30% of patients in these countries have a mutation in a known cataract causing gene, which is considerably lower than the 60%–70% reported in Caucasian cohorts. This suggests that additional cataract genes remain to be discovered in this cohort of Asian pediatric cataract patients.
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    Identification and In Vitro Expansion of Buccal Epithelial Cells
    (SAGE Publications, 2018-06-01) Ghaemi, Soraya Rasi; Delalat, Bahman; Harding, Frances Jane; Irani, Yazad; Williams, Keryn Anne; Voelcker, Nicolas Hans
    Ex vivo-expanded buccal mucosal epithelial (BME) cell transplantation has been used to reconstruct the ocular surface. Methods for enrichment and maintenance of BME progenitor cells in ex vivo cultures may improve the outcome of BME cell transplantation. However, the parameter of cell seeding density in this context has largely been neglected. This study investigates how varying cell seeding density influences BME cell proliferation and differentiation on tissue culture polystyrene (TCPS). The highest cell proliferation activity was seen when cells were seeded at 5×104 cells/cm2. Both below and above this density, the cell proliferation rate decreased sharply. Differential immunofluorescence analysis of surface markers associated with the BME progenitor cell population (p63, CK19, and ABCG2), the differentiated cell marker CK10 and connexin 50 (Cx50) revealed that the initial cell seeding density also significantly affected the progenitor cell marker expression profile. Hence, this study demonstrates that seeding density has a profound effect on the proliferation and differentiation of BME stem cells in vitro, and this is relevant to downstream cell therapy applications.