Publications by authors named "Sandra E Staffieri"

26 Publications

  • Page 1 of 1

Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry.

Ophthalmology 2021 Apr 20. Epub 2021 Apr 20.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.

Purpose: To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort.

Design: Retrospective clinical and molecular study.

Participants: All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry.

Methods: We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma.

Main Outcome Measures: The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age.

Results: A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n = 29, 23.2%) and heterozygous variants in MYOC (n = 24, 19.2%) and FOXC1 (n = 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P = 0.02).

Conclusions: We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis.
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http://dx.doi.org/10.1016/j.ophtha.2021.04.016DOI Listing
April 2021

Parent satisfaction and acceptability of telehealth consultations in pediatric ophthalmology: initial experience during the COVID-19 pandemic.

J AAPOS 2021 Mar 6. Epub 2021 Mar 6.

Department of Ophthalmology, Royal Children's Hospital, Parkville, Victoria; Department of Paediatrics, University of Melbourne, Parkville, Victoria.

Telehealth in pediatric ophthalmology has predominantly been utilized and reported in the setting of clinician-to-clinician opinion or store-and-forward of images, particularly in the diagnosis and management of retinopathy of prematurity (ROP). We present our initial experience of using a telehealth model of care to deliver real-time specialist pediatric ophthalmology services during the COVID-19 pandemic. Over a 5-week period, parents were invited to complete an anonymous survey following a telehealth ophthalmology consultation for their child. The survey explored their satisfaction, acceptance, and feedback relating to their experience. With an overall response rate of 49.4%, satisfaction was high (43.8% very satisfied; 38.2% satisfied). Most parents (71.9%) would consider telehealth for future ophthalmology consultations for their child.
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http://dx.doi.org/10.1016/j.jaapos.2020.12.003DOI Listing
March 2021

Improving parents' knowledge of early signs of paediatric eye disease: A double-blind randomized controlled trial.

Clin Exp Ophthalmol 2020 12 26;48(9):1250-1260. Epub 2020 Oct 26.

Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

Importance: Educating parents to recognize signs of eye disease and consult a healthcare professional is critical to timely diagnosis, intervention and outcomes.

Background: We evaluate the effectiveness of an eye-health information pamphlet on parents' level of concern and help-seeking intention should they hypothetically observe leukocoria or strabismus in their child.

Design: Double-blind, randomized controlled trial conducted at a metropolitan antenatal outpatient clinic.

Participants: In total, 518 pregnant women were enrolled in the study.

Methods: After completing a study-specific, pre-test survey describing hypothetical clinical scenarios at baseline, participants were randomly assigned to receive a pamphlet on either paediatric eye health (intervention) or infant play (control). The post-test survey was sent by email 2 weeks after baseline.

Main Outcome Measures: A change in the parents' level of concern if they observed leukocoria or strabismus and a change in their help-seeking intention if they hypothetically observed leukocoria or strabismus in their child.

Results: Of the 518 women, 382 (73.7%) completed the post-test survey. At follow-up, women who received the intervention were more likely to report a higher level of concern if they observed leukocoria (OR 1.711 [CI: 1.176-2.497] P = .005]) and were less likely to delay help-seeking (OR 0.560 [CI 0.382-0.817] P = .003). No change in the level of concern for strabismus was identified between the groups; however, at follow-up, women who received the intervention were less likely to delay help-seeking (OR 0.318 [CI 0.125-0.806] P = .016).

Conclusion And Relevance: Providing parents with relevant, evidence-based information can significantly improve their knowledge and positively influence help-seeking intentions if leukocoria or strabismus are observed.
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http://dx.doi.org/10.1111/ceo.13866DOI Listing
December 2020

Global Retinoblastoma Presentation and Analysis by National Income Level.

JAMA Oncol 2020 05;6(5):685-695

Imam Hussein Cancer Center, Karbala, Iraq.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.

Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis.

Design, Setting, And Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017.

Main Outcomes And Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis.

Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]).

Conclusions And Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
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http://dx.doi.org/10.1001/jamaoncol.2019.6716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047856PMC
May 2020

Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma.

Ophthalmology 2020 06 7;127(6):758-766. Epub 2020 Jan 7.

Department of Ophthalmology, Flinders University, Adelaide, Australia.

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) 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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http://dx.doi.org/10.1016/j.ophtha.2019.12.024DOI Listing
June 2020

The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort.

Clin Genet 2020 05 5;97(5):764-769. Epub 2020 Mar 5.

Department of Ophthalmology, Flinders University, Adelaide, Australia.

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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http://dx.doi.org/10.1111/cge.13722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811993PMC
May 2020

Prevalence of FOXC1 Variants in Individuals With a Suspected Diagnosis of Primary Congenital Glaucoma.

JAMA Ophthalmol 2019 04;137(4):348-355

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.

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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http://dx.doi.org/10.1001/jamaophthalmol.2018.5646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459212PMC
April 2019

Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect.

Invest Ophthalmol Vis Sci 2018 08;59(10):4054-4064

Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States.

Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait.

Methods: White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted.

Results: A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1.

Conclusions: This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.
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http://dx.doi.org/10.1167/iovs.18-24082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088800PMC
August 2018

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Nat Commun 2018 05 14;9(1):1864. Epub 2018 May 14.

Department of Ophthalmology, Flinders University, SA 5042, Adelaide, Australia.

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) 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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http://dx.doi.org/10.1038/s41467-018-03646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951816PMC
May 2018

Crowd-sourced Ontology for Photoleukocoria: Identifying Common Internet Search Terms for a Potentially Important Pediatric Ophthalmic Sign.

Transl Vis Sci Technol 2018 Feb 15;7(1):18. Epub 2018 Feb 15.

Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia.

Purpose: Leukocoria is the most common presenting sign for pediatric eye disease including retinoblastoma and cataract, with worse outcomes if diagnosis is delayed. We investigated whether individuals could identify leukocoria in photographs (photoleukocoria) and examined their subsequent Internet search behavior.

Methods: Using a web-based questionnaire, in this cross-sectional study we invited adults aged over 18 years to view two photographs of a child with photoleukocoria, and then search the Internet to determine a possible diagnosis and action plan. The most commonly used search terms and websites accessed were recorded.

Results: The questionnaire was completed by 1639 individuals. Facebook advertisement was the most effective recruitment strategy. The mean age of all respondents was 38.95 ± 14.59 years (range, 18-83), 94% were female, and 59.3% had children. An abnormality in the images presented was identified by 1613 (98.4%) participants. The most commonly used search terms were: "white," "pupil," "photo," and "eye" reaching a variety of appropriate websites or links to print or social media articles.

Conclusions: Different words or phrases were used to describe the same observation of photoleukocoria leading to a range of websites. Variations in the description of observed signs and search words influenced the sites reached, information obtained, and subsequent help-seeking intentions.

Translational Relevance: Identifying the most commonly used search terms for photoleukocoria is an important step for search engine optimization. Being directed to the most appropriate websites informing of the significance of photoleukocoria and the appropriate actions to take could improve delays in diagnosis of important pediatric eye disease such as retinoblastoma or cataract.
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http://dx.doi.org/10.1167/tvst.7.1.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815559PMC
February 2018

High-Throughput Genetic Screening of 51 Pediatric Cataract Genes Identifies Causative Mutations in Inherited Pediatric Cataract in South Eastern Australia.

G3 (Bethesda) 2017 10 5;7(10):3257-3268. Epub 2017 Oct 5.

Department of Ophthalmology, School of Medicine, Flinders University, Adelaide, South Australia 5042, Australia.

Pediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of pediatric cataract in Australian families by screening known disease-associated genes using massively parallel sequencing technology. We sequenced 51 previously reported pediatric cataract genes in 33 affected individuals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritized for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency <1% in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract-causing mutations were screened in 326 unrelated Australian controls. We detected 11 novel mutations in , , , , , , , , and ; and three previously reported cataract-causing mutations in , , and The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of pediatric cataract-associated mutations in our Australian cohort, known genes account for >60% of familial pediatric cataract in Australia, indicating that still more causative genes remain to be identified.
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http://dx.doi.org/10.1534/g3.117.300109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633377PMC
October 2017

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants.

Eur J Hum Genet 2017 06 17;25(7):839-847. Epub 2017 May 17.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, SA, Australia.

Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.
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http://dx.doi.org/10.1038/ejhg.2017.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520071PMC
June 2017

Clinical and molecular characterization of females affected by X-linked retinoschisis.

Clin Exp Ophthalmol 2015 Sep-Oct;43(7):643-7. Epub 2015 Jun 19.

Australian Inherited Retinal Disease Register & DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.

Background: X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females.

Design: Clinical and molecular characterization of male and female individuals affected with XLRS in a consanguineous family.

Participants: Consanguineous Eastern European-Australian family

Methods: Four clinically affected and nine unaffected family members were genetically and clinically characterized. Deoxyribonucleic acid (DNA) analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank.

Main Outcome Measures: Clinical and molecular characterization of the causative mutation in a consanguineous family with XLRS.

Results: By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C > T, p. R102W, was identified in all clinically diagnosed individuals analysed. The two females were homozygous for the variant, and the males were hemizygous.

Conclusion: Clinical and genetic characterization of affected homozygous females in XLRS affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans.
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http://dx.doi.org/10.1111/ceo.12541DOI Listing
April 2016

CYP1B1 copy number variation is not a major contributor to primary congenital glaucoma.

Mol Vis 2015 11;21:160-4. Epub 2015 Feb 11.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.

Purpose: To evaluate the prevalence and the diagnostic utility of testing for CYP1B1 copy number variation (CNV) in primary congenital glaucoma (PCG) cases unexplained by CYP1B1 point mutations in The Australian and New Zealand Registry of Advanced Glaucoma.

Methods: In total, 50 PCG cases either heterozygous for disease-causing variants or with no CYP1B1 sequence variants were included in the study. CYP1B1 CNV was analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA).

Results: No deletions or duplications were found in any of the cases.

Conclusion: This is the first study to report on CYP1B1 CNV in PCG cases. Our findings show that this mechanism is not a major contributor to the phenotype and is of limited diagnostic utility.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333725PMC
September 2015

Superselective intra-arterial chemotherapy for advanced retinoblastoma complicated by metastatic disease.

J AAPOS 2015 Feb;19(1):72-4

Department of Ophthalmology, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.

We present a case of a child with unilateral group E retinoblastoma (according to the International Classification of Retinoblastoma) who received superselective intra-arterial chemotherapy as primary therapy. Although the tumor showed signs of regression, the patient developed orbital metastases requiring surgical excision and chemotherapy. Eventually the affected eye progressed to total retinal detachment and required enucleation.
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http://dx.doi.org/10.1016/j.jaapos.2014.08.013DOI Listing
February 2015

Managing fetuses at high risk of retinoblastoma: lesion detection on screening MRI.

Prenat Diagn 2015 Feb 27;35(2):174-8. Epub 2014 Nov 27.

The Royal Children's Hospital, Melbourne, Victoria, Australia; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

Objective: This study aimed to describe tumour identification on magnetic resonance imaging (MRI) in a 35-week fetus with familial retinoblastoma (RB) and report the use of prenatal ultrasound (US) and MRI screening in the management of fetuses at high risk of RB.

Method: This is a retrospective review of the prenatal course and immediate postnatal findings in all children considered at high risk of RB who had prenatal imaging with both US and MRI at our institution over a 5-year period.

Results: Five patients met the inclusion criteria. No lesions were identified on US in any patients. Fetal MRI identified bilateral posterior pole lesions in one patient at 35 weeks' gestation. Of the four remaining patients, three developed lesions by 5 weeks of age. Only one fetus was delivered early following detection of RB.

Conclusion: We present the first reported case of RB detected in a high-risk fetus on screening MRI at 35 weeks' gestation. A protocol for screening this population using both imaging modalities is presented.
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http://dx.doi.org/10.1002/pd.4514DOI Listing
February 2015

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma.

Nat Genet 2014 Oct 31;46(10):1126-1130. Epub 2014 Aug 31.

Duke University, Duke Eye Center, Durham, NC, USA.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.
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http://dx.doi.org/10.1038/ng.3087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177225PMC
October 2014

Mutations in the EPHA2 gene are a major contributor to inherited cataracts in South-Eastern Australia.

PLoS One 2013 27;8(8):e72518. Epub 2013 Aug 27.

Department of Ophthalmology, Flinders University, Bedford Park, SA, Australia.

Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C>T in the EPHA2 gene and the previously reported splice mutation c.2826-9G>A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072518PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754966PMC
March 2014

Incidence and predictors of glaucoma following surgery for congenital cataract in the first year of life in Victoria, Australia.

Clin Exp Ophthalmol 2013 Sep-Oct;41(7):653-61. Epub 2013 Mar 12.

Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

Aim: To determine the incidence and predictors of glaucoma following surgery for congenital and infantile cataract in an Australian population.

Design: Retrospective cohort study.

Participants: Infants (<12 months) having had lens extraction between January 1992 and May 2006, from two tertiary referral centres.

Methods: Children with uveitis, anterior segment dysgenesis, aniridia, retinopathy of prematurity, and lens subluxation were excluded. Potential predictors of incident glaucoma were examined using Cox proportional hazards regression with adjustment for clustering between eyes.

Main Outcome Measures: Incidence and predictors of secondary glaucoma.

Results: One hundred and forty-seven eyes of 101 patients (46 bilateral cataract; 55 unilateral cataract) were included, with median follow-up of 9.9 years (range 1.2-18.9 years). Cumulative incidence of glaucoma was 32.0% for eyes (n = 47) and 30.7% (n = 31) for subjects. Incidence was higher in children with bilateral cataract (38.9 vs. 17.1%, p = 0.004). There were 3.9 cases of glaucoma per 100 person years of follow-up, the incidence rate being highest for surgery performed in the first month of life. Children with glaucoma had longer median follow-up (11.8 vs. 9.3 years, p = 0.005). Risk of glaucoma decreased with increasing months of age at operation: hazard ratio 0.79, 95% confidence interval 0.69-0.91, p = 0.001. Median visual acuity was worse in children with unilateral cataract (p < 0.001).

Conclusions: We identified an increased risk of glaucoma when cataract surgery was performed in younger infants, and in those with bilateral cataract. As glaucoma may develop over a decade following lens extraction, life-long surveillance is needed to prevent glaucoma-associated vision loss.
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http://dx.doi.org/10.1111/ceo.12067DOI Listing
February 2014

Heritability of strabismus: genetic influence is specific to eso-deviation and independent of refractive error.

Twin Res Hum Genet 2012 Oct 13;15(5):624-30. Epub 2012 Jun 13.

Centre for Eye Research Australia, Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia.

Strabismus represents a complex oculomotor disorder characterized by the deviation of one or both eyes and poor vision. A more sophisticated understanding of the genetic liability of strabismus is required to guide searches for associated molecular variants. In this classical twin study of 1,462 twin pairs, we examined the relative influence of genes and environment in comitant strabismus, and the degree to which these influences can be explained by factors in common with refractive error. Participants were examined for the presence of latent ('phoria') and manifest ('tropia') strabismus using cover-uncover and alternate cover tests. Two phenotypes were distinguished: eso-deviation (esophoria and esotropia) and exo-deviation (exophoria and exotropia). Structural equation modeling was subsequently employed to partition the observed phenotypic variation in the twin data into specific variance components. The prevalence of eso-deviation and exo-deviation was 8.6% and 20.7%, respectively. For eso-deviation, the polychoric correlation was significantly greater in monozygotic (MZ) (r = 0.65) compared to dizygotic (DZ) twin pairs (r = 0.33), suggesting a genetic role (p = .003). There was no significant difference in polychoric correlation between MZ (r = 0.55) and DZ twin pairs (r = 0.53) for exo-deviation (p = .86), implying that genetic factors do not play a significant role in the etiology of exo-deviation. The heritability of an eso-deviation was 0.64 (95% CI 0.50-0.75). The additive genetic correlation for eso-deviation and refractive error was 0.13 and the bivariate heritability (i.e., shared variance) was less than 1%, suggesting negligible shared genetic effect. This study documents a substantial heritability of 64% for eso-deviation, yet no corresponding heritability for exo-deviation, suggesting that the genetic contribution to strabismus may be specific to eso-deviation. Future studies are now needed to identify the genes associated with eso-deviation and unravel their mechanisms of action.
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http://dx.doi.org/10.1017/thg.2012.22DOI Listing
October 2012

Familial retinal detachment associated with COL2A1 exon 2 and FZD4 mutations.

Clin Exp Ophthalmol 2012 Jul 19;40(5):476-83. Epub 2012 Jun 19.

Centre for Eye Research Australia, University of Melbourne, Department of Ophthalmology Vitreo-retinal Unit, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria.

Background:   To characterize the clinical and genetic abnormalities within two Australian pedigrees with high incidences of retinal detachment and visual disability.

Design:   Prospective review of two extended Australian pedigrees with high rates of retinal detachment.

Participants:   Twenty-two family members from two extended Australian pedigrees with high rates of retinal detachment were examined.

Methods:   A full ophthalmic history and examination were performed, and DNA was analysed by linkage analysis and mutation screening.

Main Outcome Measures:   Characterization of a causative hereditary gene mutation in each family.

Results:   All affected family members of one pedigree carried a C192A COL2A1 exon 2 mutation. None of the affected family members had early-onset arthritis, hearing abnormalities, abnormal clefting or facial features characteristic of classical Stickler syndrome. All affected members of the familial exudative vitreoretinopathy pedigree carried a 957delG FZD4 mutation.

Conclusions:   Patients with retinal detachment and a positive family history should be investigated for heritable conditions associated with retinal detachment such as Stickler syndrome and familial exudative vitreoretinopathy. The absence of non-ocular features of Stickler syndrome should raise the possibility of mutations in exon 2 of COL2A1. Similarly, late-onset familial exudative vitreoretinopathy may appear more like a rhegmatogenous detachment and not be correctly diagnosed. When a causative gene mutation is identified, cascade genetic screening of the family will facilitate genetic counselling and screening of high-risk relatives, allowing targeted management of the pre-detachment changes in affected patients.
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http://dx.doi.org/10.1111/j.1442-9071.2012.02804.xDOI Listing
July 2012

Telemedicine model to prevent blindness from familial glaucoma.

Clin Exp Ophthalmol 2011 Nov 27;39(8):760-5. Epub 2011 Apr 27.

Centre for Eye Research Australia, University of Melbourne, Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria.

Background: To develop, implement and evaluate a telemedicine model to reduce glaucoma blindness through the early detection of undiagnosed glaucoma in high-risk individuals.

Design: Prospective study, private ophthalmology practice and public outpatient clinics in Tasmania.

Participants: One hundred and thirty-three individuals with primary open-angle glaucoma were invited to enrol their first-degree relatives (FDRs) to undergo an eye examination. Within the study period, 211 FDRs were available for examination.

Methods: A registered nurse was trained to perform the required assessments. Clinical data were entered into a purpose-built database, converted to a portable document format and graded offsite by an ophthalmologist to determine the presence, absence or risk of developing glaucoma. Participants were notified of the grading result and recommendations for review.

Main Outcome Measures: Incidence of undiagnosed glaucoma in a high-risk population.

Results: Previously undiagnosed glaucoma was identified in 5% of those examined. For every 19 participants screened, one new case of previously undiagnosed case of glaucoma was identified. Additionally 15% of participants showed suspicious signs of glaucoma, and 6% had ocular hypertension.

Conclusions: A telemedicine model is an efficient method for screening, grading and notifying participants of examination results. Nurses can be adequately trained to undertake the initial screening examinations, with grading of the results performed offsite by a suitably qualified ophthalmologist. Targeted screening for glaucoma increases the yield of identifying individuals with undiagnosed glaucoma or those at greatest risk. Cost efficiencies for this model of glaucoma screening should be further explored and implemented to prevent blindness from familial glaucoma.
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http://dx.doi.org/10.1111/j.1442-9071.2011.02556.xDOI Listing
November 2011

Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked autosomal dominant optic atrophy.

PLoS One 2011 22;6(6):e21347. Epub 2011 Jun 22.

Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021347PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120866PMC
November 2011

Rock, paper and scissors? Traumatic paediatric cataract in Victoria 1992-2006.

Clin Exp Ophthalmol 2010 Apr;38(3):237-41

Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, 32 Gisborne Street, East Melbourne, Vic. 3002, Australia.

Background: To review visual acuity outcomes from paediatric traumatic cataract and examine the mechanisms by which they occur.

Methods: A retrospective review of paediatric patients (aged less than 18 years) who underwent lens surgery following ocular trauma, between 1992 and 2006 at the Royal Children's Hospital and Royal Victorian Eye and Ear Hospital in Melbourne. Data collected included gender, mechanism of injury, wound type, age at injury, age at surgery, refractive rehabilitation, complications and visual acuity outcome.

Results: A total of 74 patients (75% male) were identified over the 15-year period, representing an incidence of 4.9 cases per year. The mean age at injury was 7.5 years. Sixty-five cataracts (88%) followed a penetrating eye injury, whereas only nine patients (12%) developed cataract after known blunt trauma. Fourteen patients (19%) underwent lensectomy at the time of primary wound repair and 45 patients (61%) underwent primary intraocular lens (IOL) implantation. Visual acuity outcomes ranged from 6/5 to no perception of light. Twenty-five patients (34%) achieved 6/12 or better in the injured eye, 23 patients (31%) achieved between 6/15 and 6/60, and 14 patients (19%) had visual acuity of less than 6/60. Twelve patients (16%) were lost to follow-up.

Conclusion: In a paediatric population, cataract formation as a result of trauma requiring lensectomy is not uncommon. Males are more likely to suffer from such injury. A variety of sharp and blunt objects are the primary mechanism by which the injury is sustained with variable visual outcomes.
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http://dx.doi.org/10.1111/j.1442-9071.2010.02236.xDOI Listing
April 2010