Myocilin Mutations in Patients With Normal-Tension Glaucoma

Wallace L M Alward; Carly van der Heide; Cheryl L Khanna; Ben R Roos; Sobha Sivaprasad; Jason Kam; Robert Ritch; Andrew Lotery; Robert P Igo, Jr; Jessica N Cooke Bailey; Edwin M Stone; Todd E Scheetz; Young H Kwon; Louis R Pasquale; Janey L Wiggs; John H Fingert

doi:10.1001/jamaophthalmol.2019.0005

. 2019 Feb 28;137(5):559–563. doi: 10.1001/jamaophthalmol.2019.0005

Myocilin Mutations in Patients With Normal-Tension Glaucoma

Wallace L M Alward ^1,², Carly van der Heide ^1,², Cheryl L Khanna ³, Ben R Roos ^1,², Sobha Sivaprasad ^4,⁵, Jason Kam ⁶, Robert Ritch ⁷, Andrew Lotery ⁸, Robert P Igo Jr ⁹, Jessica N Cooke Bailey ^9,¹⁰, Edwin M Stone ^1,², Todd E Scheetz ^1,², Young H Kwon ^1,², Louis R Pasquale ¹¹, Janey L Wiggs ¹¹, John H Fingert ^1,^2,^✉, for the NEIGHBORHOOD Consortium

¹Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City

²Institute for Vision Research, University of Iowa, Iowa City

³Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota

⁴Moorfields Eye Hospital, London, England

⁵Kings College Hospital, London, England

⁶Kaiser Permanente, Seattle, Washington

⁷Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York

⁸Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, England

⁹Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio

¹⁰Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio

¹¹Massachusetts Eye and Ear Infirmary, Harvard University, Boston

Group Information: The members of the NEIGHBORHOOD Consortium are listed at the end of this article.

Accepted for Publication: December 22, 2018.

^✉

Corresponding Author: John H. Fingert, MD, PhD, 3111B Medical Education Research Facility, University of Iowa, 275 Newton Rd, Iowa City, IA 52242 (john-fingert@uiowa.edu).

Published Online: February 28, 2019. doi:10.1001/jamaophthalmol.2019.0005

Author Contributions: Dr Fingert had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kam.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: van der Heide, Ritch, Cooke Bailey, Pasquale, Fingert.

Critical revision of the manuscript for important intellectual content: Alward, van der Heide, Khanna, Roos, Sivaprasad, Kam, Ritch, Lotery, Igo, Stone, Scheetz, Kwon, Wiggs, Fingert.

Statistical analysis: van der Heide, Roos, Kam, Igo, Cooke Bailey, Scheetz, Fingert.

Obtained funding: Fingert.

Administrative, technical, or material support: Alward, Roos, Sivaprasad, Lotery, Stone, Scheetz, Kwon, Fingert.

Supervision: Ritch, Pasquale, Wiggs.

Conflict of Interest Disclosures: Dr Pasquale reports receiving grants support for the National Eye Institute and personal fees from Eyenovia and Basuch+Lomb Inc. Dr Ritch reports receiving personal fees from Aeon Astron, ISonic Medical, and Santen Pharmaceuticals and consulting fees from Diopsys Inc, GLIA LLC, Guardion Health Sciences, Intelon Optics, Axim Biotechnologies Inc, Miotech, and Glauconix Inc. Dr Sivaprasad reports receiving grants and personal fees from Boehringer Inglehein, Roche, Novartis, Allergan, and Bayer and personal fees from Heidelberg Engineering. No other disclosures are reported.

Funding/Support: The research in this report was supported in part by National Institutes of Health grants R01EY023512, R01EY022305, R01EY015473, and P30EY014104 and Donald Heineking and the Hadley-Carver Chair in Glaucoma.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Group Information: The members of the NEIGHBORHOOD Consortium are Jessica N. Cooke Bailey; Louis R. Pasquale, MD; Janey L. Wiggs, MD, PhD; John H. Fingert, MD, PhD; and Rand Allingham MD, Duke University Medical Center; Murray Brilliant, PhD, Marshfield Clinic Research Foundation; Don Budenz, MD, MPH, University of North Carolina, Chapel Hill; Jessica Cooke Bailey, PhD, Case Western Reserve University School of Medicine; John Fingert, MD, PhD, University of Iowa; Douglas Gaasterland, MD, Eye Doctors of Washington; Teresa Gaasterland, PhD, University of California at San Diego; Jonathan L. Haines, PhD, Case Western Reserve University School of Medicine; Michael Hauser, PhD, Duke University Medical Center; Rob Igo, PhD, Case Western Reserve University School of Medicine; Jae Hee Kang, PhD, Harvard Medical School; Peter Kraft, PhD, Harvard School of Public Health; Richard Lee, MD, PhD, University of Miami Miller School of Medicine; Paul Lichter, MD, MS, University of Michigan; Yutao Liu, MD, PhD, Georgia Regents University; Syoko Moroi, MD, PhD, University of Michigan; Louis R. Pasquale, MD, Icahn School of Medicine at Mount Sinai; Margaret Pericak-Vance, PhD, University of Miami Miller School of Medicine; Anthony Realini, MD, MPH, West Virginia University Eye Institute; Doug Rhee, MD, Case Western Reserve University School of Medicine; Julia R. Richards, PhD, University of Michigan; Robert Ritch, MD, New York Eye and Ear Infirmary of Mount Sinai; Joel Schuman, MD, New York University School of Medicine; William K. Scott, PhD, University of Miami Miller School of Medicine; Kuldev Singh, MD, MPH, Stanford University School of Medicine; Arthur Sit, MD, Mayo Clinic; Douglas Vollrath, MD, PhD, Stanford University School of Medicine; Janey L. Wiggs, MD, PhD, Harvard Medical Schools; Robert N. Weinreb, MD, University of California, San Diego; Gadi Wollstein, MD, New York University School of Medicine; Don Zack, MD, PhD, Johns Hopkins University Hospital.

^✉

Corresponding author.

PMCID: PMC6512256 PMID: 30816940

Key Points

Question

Is the most common, known glaucoma-causing mutation, p.Gln368Ter in the myocilin gene, associated with glaucoma that occurs with intraocular pressures (IOPs) of 21 mm Hg or lower (normal-tension glaucoma) as well as glaucoma that occurs with high IOPs?

Findings

In this case-control study of 1333 patients and 4758 controls, the p.Gln368Ter mutation was detected at a significantly higher frequency in patients with normal-tension glaucoma than in control participants.

Meaning

These findings suggest that myocilin mutations are associated with glaucoma that occurs with a broader range of IOP than previously recognized, including individuals with pressures that are 21 mm Hg or lower.

Abstract

Importance

Mutations in the myocilin (MYOC) gene are the most common molecularly defined cause of primary open-angle glaucoma that typically occurs in patients with high intraocular pressures (IOP). One MYOC mutation, p.Gln368Ter, has been associated with as many as 1.6% of primary open-angle glaucoma cases that had a mean maximum recorded IOP of 30 mm Hg. However, to our knowledge, the role of the p.Gln368Ter mutation in patients with normal-tension glaucoma (NTG) with an IOP of 21 mm Hg or lower has not been investigated.

Objective

To evaluate the role of the p.Gln368Ter MYOC mutation in patients with NTG.

Design, Setting, and Participants

In this case-control study of the prevalence of the p.Gln368Ter mutation in patients with NTG, cohort 1 was composed of 772 patients with NTG and 2152 controls from the United States (Iowa, Minnesota, and New York) and England and cohort 2 was composed of 561 patients with NTG and 2606 controls from the Massachusetts Eye and Ear Infirmary and the NEIGHBORHOOD consortium. Genotyping was conducted using real-time polymerase chain reaction that was confirmed with Sanger sequencing, the imputation of genome-wide association study data, or an analysis of whole-exome sequence data. Data analysis occurred between April 2007 and April 2018.

Main Outcomes and Measures

Comparison of the frequency of the p.Gln368Ter MYOC mutation between NTG cases and controls with the Fisher exact test.

Results

Of 6091 total participants, 3346 (54.9%) were women and 5799 (95.2%) were white. We detected the p.Gln368Ter mutation in 7 of 772 patients with NTG (0.91%) and 7 of 2152 controls (0.33%) in cohort 1 (P = .03). In cohort 2, we detected the p.Gln368Ter mutation in 4 of 561 patients with NTG (0.71%) and 10 of 2606 controls (0.38%; P = .15). When the cohorts were analyzed as a group, the p.Gln368Ter mutation was associated with NTG (odds ratio, 2.3; 95% CI, 0.98-5.3; P = .04).

Conclusions and Relevance

In cohorts 1 and 2, the p.Gln368Ter mutation in MYOC was found in patients with IOPs that were 21 mm Hg or lower (NTG), although at a frequency that is lower than previously detected in patients with higher IOP. These data suggest that the p.Gln368Ter mutation may be associated with glaucoma in patients with normal IOPs as well as in patients with IOPs that are greater than 21 mm Hg.

This case-control study evaluates the association of the GLN368Ter mutation in the myocilin gene with glaucoma in patients with normal-tension glaucoma in the United States and England.

Introduction

Primary open-angle glaucoma (POAG) is a leading cause of visual disability and has a significant genetic basis. Three genes, myocilin (MYOC), optineurin (OPTN), and TANK binding kinase 1 (TBK1), are known to be associated with some cases of glaucoma with little influence from other genetic factors.^1,2,3 Mutations in MYOC are responsible for 3% to 4% of POAG cases that typically have a high intraocular pressure (IOP) (>21 mm Hg).^1,4 One MYOC mutation, p.Gln368Ter (also known as Gln368Stop), has been associated with 1.6% of POAG cases with high IOP (>21 mm Hg).⁵ In this article, we investigate the role of MYOC in patients with normal-tension glaucoma (NTG) with an IOP 21 mm Hg or lower by testing cohorts of patients with NTG and controls for the most common MYOC mutation, p.Gln368Ter.

Methods

Study Participants

Participants gave informed consent and the University of Iowa institutional review board approved the research. The criteria for NTG were glaucomatous optic nerve damage and visual field loss with a maximum recorded IOP of 21 mm Hg or lower.^3,4 Patients with secondary glaucoma were excluded. Patients with mutations in TBK1 or OPTN were excluded. The criteria for healthy control participants included being older than 50 years, an IOP of 21 mm Hg or lower, failure to meet the criteria for glaucoma, and an examination by an ophthalmologist. Another cohort from the Retina Clinic at the University of Iowa with no known history of glaucoma (n = 1434) was used as a population control. Cohort 1 was composed of 406 patients with NTG, 528 healthy controls, and 1434 population control participants from Iowa; 93 patients with NTG and 37 healthy controls from Minnesota; 125 patients with NTG from New York; and 148 patients with NTG and 153 healthy controls from England.

The POAG cases in the NEIGHBORHOOD Consortium or from the Massachusetts Eye and Ear Infirmary were classified as NTG if the highest known IOP at or before enrollment was less than 22 mm Hg. Patients with glaucoma with an IOP of less than 22 mm Hg who were receiving IOP-lowering treatment at enrollment were also classified as having NTG if there were no recorded IOPs that were greater than 22 mm Hg before treatment. Pretreatment IOP was available for 376 (67%) of the NEIGHBORHOOD cases overall and was available for all of the cases classified as NTG. Control participants had an IOP of 21 mm Hg or lower without glaucoma features.⁶ Cohort 2 was composed of 166 patients with NTG and 344 healthy controls from Massachusetts Eye and Ear Infirmary and 395 patients with NTG and 2262 healthy controls from the NEIGHBORHOOD consortium.

Genotyping

Whole-exome sequencing results in cohort 1 had been obtained from 134 patients with NTG, 362 healthy controls, and 1434 population controls as previously described⁷ and the presence of the p.Gln368Ter mutation was assessed by inspection. The remainder of cohort 1 (638 patients with NTG and 356 healthy controls) was tested for the p.Gln368Ter mutation using a real-time polymerase chain reaction TaqMan assay (Applied Biosystems) following the manufacturer’s protocol. All instances of p.Gln368Ter were confirmed with Sanger sequencing as previously described.⁵

The presence or absence of the p.Gln368Ter mutation in MYOC among cohort 2 members was inferred from the posterior probabilities imputed from genome-wide association study genotypes as previously described,⁸ removing minor allele frequency filters. IMPUTE2⁹ assigned a heterozygous p.Gln368Ter genotype (rs74315329) based on flanking marker genotypes using the 1000 Genomes Project as a reference panel. A posterior probability of 0.7 or more was used as a threshold to assign p.Gln368Ter. DNA was not available for Sanger sequencing to confirm imputed results. However, a similar approach reported 100% sensitivity, 99.9% specificity, and 95.7% positive predictive value for identifying p.Gln368Ter with imputation.⁸ The frequency of p.Gln368Ter mutation was compared between NTG cases and controls using the Fisher exact test with a threshold for significance of P < .05.

Results

Genetic Analyses

We evaluated the role of the p.Gln368Ter mutation in MYOC in NTG by assessing its frequency in 2 cohorts of patients with NTG and control participants. We used real-time polymerase chain reaction, Sanger sequencing, whole-exome sequencing, and the imputation of genome-wide association study genotypes to test for the p.Gln368Ter mutation.

In cohort 1 (Table 1), we detected the p.Gln368Ter mutation in 7 of 772 patients with NTG (0.91%) and 7 of 2152 controls (0.33%) (odds ratio [OR], 3.2; 95% CI, 0.96-10.8; P = .03). In cohort 2 (Table 1), we detected the p.Gln368Ter mutation in 4 of 561 patients with NTG (0.71%) and 10 of 2606 controls (0.38%) (OR, 2.3; 95% CI, 0.52-7.9; P = .15). When cohorts 1 and 2 were pooled, p.Gln368Ter was observed in 11 of 1333 patients with NTG (0.83%) and 17 of 4758 control participants (0.36%) (OR, 2.3; 95% CI, 0.98-5.3; P = .04).

Table 1. Patients With NGT With p.Gln368Ter Mutations.

Participants	Cohort 1							Cohort 2					Cohorts 1 and 2
	No. (%)					Odds Ratio (95% CI)	P Value	No. (%)			Odds Ratio (95% CI)	P Value	No. (%)	Odds Ratio (95% CI)	P Value
	Iowa	Minnesota	New York	England	Total	Odds Ratio (95% CI)	P Value	Massachusetts Eye and Ear Infirmary	NEIGHBORHOOD Consortium	Total	Odds Ratio (95% CI)	P Value	Total	Odds Ratio (95% CI)	P Value
Patients with NTG	4/406 (1.0)	2/93 (2.2)	0/125	1/148 (0.7)	7/772 (0.9)	3.2 (0.96-10.8)	.03	0/166 (0)	4/395 (1.0)	4/561 (0.7)	2.3 (0.52-7.9)	.15	11/1333 (0.8)	2.3 (0.98-5.3)	.04
Control participants	5/1962 (0.3)	1/37 (2.7)	NA	1/153 (0.7)	7/2152 (0.3)	3.2 (0.96-10.8)	.03	1/344 (0.3)	9/2262 (0.4)	10/2606 (0.4)	2.3 (0.52-7.9)	.15	17/4758 (0.4)	2.3 (0.98-5.3)	.04

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Abbreviations: NA, not applicable; NTG, normal-tension glaucoma.

Clinical Features of Patients With NTG With p.Gln368Ter Mutations

We examined the clinical features of the 11 patients with NTG with p.Gln368Ter mutations (Table 2). The mean (SD) maximum IOP in patients with NTG with the p.Gln368Ter mutation from cohort 1 was 20.0 (1.4) mm Hg (range, 17-21 mm Hg). Disc photographs and visual field test results from a representative case are shown in the eFigure in the Supplement. The mean (SD) central corneal thickness of patients with p.Gln368Ter mutations from both cohorts was 557 (39.3) μm (range, 469-620 microns). A disc hemorrhage was observed in 1 patient, while 6 patients had a family history of glaucoma in a first-degree relative.

Table 2. Clinical Features of 7 Patients With NTG With p.Gln368Ter Mutations.

Characteristic	Cohort 1								Cohort 2
Characteristic	Iowa				Minnesota		England	Mean (SD)	NEIGHBORHOOD Consortium				Mean (SD)
Patient ID	2087-1	2393-1	2332-1	1132-1	1234602412	1305706063	92		NA1125	NA1375	NF7503	NI01430
Max IOP OD, mm Hg	20	20	15	20	20	20	21	20.0 (1.4)	17	20	14	13	15.8 (2.8)
Max IOP OS, mm Hg	21	21	17	20	20	NA^a	20	20.0 (1.4)	18	20	13	13	15.8 (2.8)
Diurnal IOP measured	No	Yes	No	Yes	No	No	No	NAp	No	No	No	No	NAp
Central corneal thickness OD, microns	566	585	483	NA	547	552	NA	548 (42.3)	550	572	620	NA	573 (30.9)
Central corneal thickness OS, microns	566	607	469	NA	559	546	NA	548 (42.3)	549	546	600	NA	573 (30.9)
History of disc hemorrhage	Yes	Not noted	Not noted	Not noted	Not noted	Not noted	Not noted	NAp	Not noted	Not noted	Not noted	Not noted	NAp
Family history of glaucoma (first-degree relative)	Yes	Yes	Yes	Yes	Yes	No	Yes	NAp	No	No	No	NA	NAp

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Abbreviations: IOP, intraocular pressure; NA, not available; NAp, not applicable; NTG, normal-tension glaucoma.

^{^a}

Patient 1305706063 had a central retinal vein occlusion and developed neovascular glaucoma in the left eye after receiving a diagnosis of NTG. The IOP measurements before the vein occlusion were not available.

Discussion

MYOC was discovered to be associated with glaucoma via genetic studies of pedigrees with juvenile-onset primary open-angle glaucoma (JOAG). The patients with JOAG in these studies were found to harbor a set of MYOC mutations (GLY364VAL, THR377MET, TYR437HIS, and ILE477ASN) that were associated with mean maximum IOPs of 36, 31, 44, and 40 mm Hg, respectively.⁴ The p.Gln368Ter mutation has been associated with adult-onset POAG with high IOP (mean maximum IOP of 26-30 mm Hg).^4,10,11 As a result, MYOC-associated glaucoma has been considered synonymous with glaucoma that occurs with high IOP.

Isolated instances of MYOC mutations have been reported in patients with NTG. Alward et al¹² reported a TRP286ARG mutation in 1 patient with NTG. This mutation had been reported in 3 other patients with POAG with high IOP and in 1 case of JOAG with high IOP.^5,13,14 One occurrence of a p.Gln368Ter mutation was detected in a patient with NTG from Germany.¹⁵ These observations, coupled with the 11 cases of patients with NTG with the p.Gln368Ter mutation in this article, provide evidence that the MYOC gene is associated with glaucoma across a broader range of IOP than was previously recognized.

Limitations

This study had limitations. Pretreatment IOPs were not available for all patients with NTG. Also, variation in central corneal thickness influences IOP measurement and could potentially have led to a misdiagnosis of NTG for some patients. Similarly, some patients who received a diagnosis of NTG might have had an unrecognized IOP of more than 21 mm Hg because of diurnal variation or infrequent testing. This study should be evaluated in the context of these limitations.

Conclusions

One interpretation of these data is that the p.Gln368Ter mutation may be associated with glaucoma with peak IOP less than an arbitrary threshold of 21 mm Hg (NTG) or greater than this threshold (POAG). Rather than separate the glaucoma associated with the p.Gln368Ter mutation into these categories of NTG or high-tension glaucoma, it may be more useful to note that MYOC-associated glaucoma occurs over a range of IOPs with a prevalence that increases with maximum IOP. However, ophthalmologists tend to describe open-angle glaucoma as NTG if the maximum IOP is 21 mm Hg or lower. With such definitions, the p.Gln368Ter mutation in MYOC may be responsible for up to 0.83% of NTG cases, making it the third most common, known cause of NTG behind OPTN and TBK1.^2,3

Supplement.

eFigure. Clinical features of a patient with NTG at age 65 years.

Click here for additional data file.^{(471.3KB, pdf)}

References

1.Stone EM, Fingert JH, Alward WLM, et al. Identification of a gene that causes primary open angle glaucoma. Science. 1997;275(5300):668-670. doi: 10.1126/science.275.5300.668 [DOI] [PubMed] [Google Scholar]
2.Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;295(5557):1077-1079. doi: 10.1126/science.1066901 [DOI] [PubMed] [Google Scholar]
3.Fingert JH, Robin AL, Stone JL, et al. Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum Mol Genet. 2011;20(12):2482-2494. doi: 10.1093/hmg/ddr123 [DOI] [PMC free article] [PubMed] [Google Scholar]
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13.Mendoza-Reinoso V, Patil TS, Guevara-Fujita ML, et al. Novel and known MYOC exon 3 mutations in an admixed Peruvian primary open-angle glaucoma population. Mol Vis. 2012;18:2067-2075. [PMC free article] [PubMed] [Google Scholar]
14.Souzeau E, Burdon KP, Dubowsky A, et al. Higher prevalence of myocilin mutations in advanced glaucoma in comparison with less advanced disease in an Australasian disease registry. Ophthalmology. 2013;120(6):1135-1143. doi: 10.1016/j.ophtha.2012.11.029 [DOI] [PubMed] [Google Scholar]
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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eFigure. Clinical features of a patient with NTG at age 65 years.

Click here for additional data file.^{(471.3KB, pdf)}

[ebr190001r1] 1.Stone EM, Fingert JH, Alward WLM, et al. Identification of a gene that causes primary open angle glaucoma. Science. 1997;275(5300):668-670. doi: 10.1126/science.275.5300.668 [DOI] [PubMed] [Google Scholar]

[ebr190001r2] 2.Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;295(5557):1077-1079. doi: 10.1126/science.1066901 [DOI] [PubMed] [Google Scholar]

[ebr190001r3] 3.Fingert JH, Robin AL, Stone JL, et al. Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum Mol Genet. 2011;20(12):2482-2494. doi: 10.1093/hmg/ddr123 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ebr190001r4] 4.Alward WL, Fingert JH, Coote MA, et al. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med. 1998;338(15):1022-1027. doi: 10.1056/NEJM199804093381503 [DOI] [PubMed] [Google Scholar]

[ebr190001r5] 5.Fingert JH, Héon E, Liebmann JM, et al. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet. 1999;8(5):899-905. doi: 10.1093/hmg/8.5.899 [DOI] [PubMed] [Google Scholar]

[ebr190001r6] 6.Wiggs JL, Hauser MA, Abdrabou W, et al. The NEIGHBOR consortium primary open-angle glaucoma genome-wide association study: rationale, study design, and clinical variables. J Glaucoma. 2013;22(7):517-525. doi: 10.1097/IJG.0b013e31824d4fd8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ebr190001r7] 7.Stone EM, Andorf JL, Whitmore SS, et al. Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease. Ophthalmology. 2017;124(9):1314-1331. doi: 10.1016/j.ophtha.2017.04.008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ebr190001r8] 8.Gharahkhani P, Burdon KP, Hewitt AW, et al. Accurate imputation-based screening of Gln368Ter myocilin variant in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2015;56(9):5087-5093. doi: 10.1167/iovs.15-17305 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ebr190001r9] 9.Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5(6):e1000529. doi: 10.1371/journal.pgen.1000529 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ebr190001r10] 10.Allingham RR, Wiggs JL, De La Paz MA, et al. Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1998;39(12):2288-2295. [PubMed] [Google Scholar]

[ebr190001r11] 11.Craig JE, Baird PN, Healey DL, et al. Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier. Ophthalmology. 2001;108(9):1607-1620. doi: 10.1016/S0161-6420(01)00654-6 [DOI] [PubMed] [Google Scholar]

[ebr190001r12] 12.Alward WLM, Kwon YH, Khanna CL, et al. Variations in the myocilin gene in patients with open-angle glaucoma. Arch Ophthalmol. 2002;120(9):1189-1197. doi: 10.1001/archopht.120.9.1189 [DOI] [PubMed] [Google Scholar]

[ebr190001r13] 13.Mendoza-Reinoso V, Patil TS, Guevara-Fujita ML, et al. Novel and known MYOC exon 3 mutations in an admixed Peruvian primary open-angle glaucoma population. Mol Vis. 2012;18:2067-2075. [PMC free article] [PubMed] [Google Scholar]

[ebr190001r14] 14.Souzeau E, Burdon KP, Dubowsky A, et al. Higher prevalence of myocilin mutations in advanced glaucoma in comparison with less advanced disease in an Australasian disease registry. Ophthalmology. 2013;120(6):1135-1143. doi: 10.1016/j.ophtha.2012.11.029 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Myocilin Mutations in Patients With Normal-Tension Glaucoma

Wallace L M Alward, MD

Carly van der Heide, BS

Cheryl L Khanna, MD

Ben R Roos, BS

Sobha Sivaprasad, FRCS

Jason Kam, MD

Robert Ritch, MD

Andrew Lotery, MD

Robert P Igo Jr, PhD

Jessica N Cooke Bailey, PhD

Edwin M Stone, MD, PhD

Todd E Scheetz, PhD

Young H Kwon, MD, PhD

Louis R Pasquale, MD

Janey L Wiggs, MD, PhD

John H Fingert, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Participants

Genotyping

Results

Genetic Analyses

Table 1. Patients With NGT With p.Gln368Ter Mutations.

Clinical Features of Patients With NTG With p.Gln368Ter Mutations

Table 2. Clinical Features of 7 Patients With NTG With p.Gln368Ter Mutations.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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