Identification of a novel <i>MYOC</i> variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure

Criscione, June; Ji, Weizhen; Jeffries, Lauren; McGrath, James; Soloway, Scott M.; Pusztai, Lajos; Lakhani, Saquib A.

doi:10.1101/mcs.a004374

Cited by 7 publications

(5 citation statements)

References 30 publications

(35 reference statements)

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“…The MYOC gene encodes the myocilin protein, also known as the trabecular meshwork glucocorticoid-inducible response (TIGR) protein, which in the eye is expressed primarily in trabecular meshwork tissue and thought to be an important contributor to the regulation of intraocular pressure [ 196 ]. Homozygous and heterozygous missense MYOC variants have been implicated in case reports and cases series of bilateral PCG and JOAG [ 156 , 160 ] Some common variants identified include the missense p.P370L [ 163 , 168 , 169 ] and p.Q48H [ 157 , 159 ] variants. Of note, the missense p.Q48H variant is thought to contribute to a consequential proportion of cases in India, with that variant alone found in 2.5% of PCG cases in an observational study in India [ 158 ].…”

Section: Discussion/summary Of Evidencementioning

confidence: 99%

Genetic changes and testing associated with childhood glaucoma: A systematic review

Kumar,

Han,

Oatts

2024

PLoS ONE

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Many forms of childhood glaucoma have been associated with underlying genetic changes, and variants in many genes have been described. Currently, testing is variable as there are no widely accepted guidelines for testing. This systematic review aimed to summarize the literature describing genetic changes and testing practices in childhood glaucoma. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) 2020 guidelines and registered with Prospero (ID CRD42023400467). A comprehensive review of Pubmed, Embase, and Cochrane databases was performed from inception through March 2, 2023 using the search terms: (glaucoma) AND (pediatric OR childhood OR congenital OR child OR infant OR infantile) AND (gene OR genetic OR genotype OR locus OR genomic OR mutation OR variant OR test OR screen OR panel). Information was extracted regarding genetic variants including genotype-phenotype correlation. Risk of bias was assessed using the Newcastle-Ottawa Scale. Of 1,916 records screened, 196 studies met inclusion criteria and 53 genes were discussed. Among study populations, mean age±SD at glaucoma diagnosis was 8.94±9.54 years and 50.4% were male. The most common gene discussed was CYP1B1, evaluated in 109 (55.6%) studies. CYP1B1 variants were associated with region and population-specific prevalence ranging from 5% to 86% among those with primary congenital glaucoma. MYOC variants were discussed in 31 (15.8%) studies with prevalence up to 36% among patients with juvenile open angle glaucoma. FOXC1 variants were discussed in 25 (12.8%) studies, which demonstrated phenotypic severity dependent on degree of gene expression and type of mutation. Overall risk of bias was low; the most common domains of bias were selection and comparability. Numerous genes and genetic changes have been associated with childhood glaucoma. Understanding the most common genes as well as potential genotype-phenotype correlation has the potential to improve diagnostic and prognostic outcomes for children with glaucoma.

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Section: Discussion/summary Of Evidencementioning

confidence: 99%

Genetic changes and testing associated with childhood glaucoma: A systematic review

Kumar,

Han,

Oatts

2024

PLoS ONE

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“…She had a strong family history of glaucoma in multiple first-degree relatives, and she was found to share a novel variant of the MYOC gene (NM_000261.2: c.1153G>A, p.Glu385), as described above, with her father, sister, and brother under a research protocol completed at the Yale Center for Genome Analysis. 7 The patient had previously undergone successful trabeculectomy with mitomycin C in the right eye (OD) in 2014 and selective laser trabeculoplasty (SLT) in the left eye in early 2018 that failed to significantly lower her IOP. Her maximum recorded IOP was 40 mmHg OD and 46 mmHg OS.…”

Section: Case Presentationmentioning

confidence: 99%

“…5,6 There are currently 280 identified MYOC mutations, 37.86% of which have been associated with the development of glaucoma. [6][7][8] These mutations are thought to cause aqueous outflow obstruction at the level of the TM. Missense mutations make up 85.9% of glaucoma-related MYOC mutations, most of which arise within the olfactomedin (OLF) domain present on exon 3 of MYOC.…”

Section: Introductionmentioning

confidence: 99%

“…Glu385Lys exchanges a highly-conserved negatively-charged glutamic acid for a positively-charged lysine amino acid. 7 This substitution causes a conformational change at the level of the OLF domain, which disrupts proper processing and delivery of the MYOC protein to the extracellular matrix. Studies hypothesize that misfolded MYOC proteins are then retained within the endoplasmic reticulum (ER) of TM cells.…”

Section: Introductionmentioning

confidence: 99%

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Case Report: Reversal and subsequent return of optic disc cupping in a myocilin (MYOC) gene-associated severe Juvenile Open-Angle Glaucoma (JOAG) patient

et al. 2022

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To our knowledge, this case report describes the first instance of reversal of glaucomatous optic nerve cupping in a young adult with a rare form of juvenile open-angle glaucoma (JOAG) associated with a novel variant of the myocilin gene (MYOC). This 25-year-old woman with severe-stage MYOC-associated JOAG presented with blurry vision and intermittent pain in her left eye. She had a strong family history of glaucoma in multiple first-degree relatives with an identified novel variant of MYOC. Examination revealed intraocular pressures (IOPs) of 10 mmHg OD and 46 mmHg OS, with cup-to-disc ratios of 0.90 and 0.80. The patient experienced substantial reversal of optic disc cupping OS following dramatic IOP reduction with trabeculectomy, and subsequently experienced a return of cupping after an IOP spike 15 months postoperatively. The reversal of cupping did not correspond to any changes in the patient’s visual field. After an initial decrease in retinal nerve fiber layer (RNFL) thickness, RNFL remained stable for over 2 years after trabeculectomy as seen on Optical Coherence Tomography (OCT). This case suggests reversal of cupping can occur well into adulthood in a MYOC-associated JOAG patient, and it demonstrates the potential bidirectionality of this phenomenon. Moreover, it suggests that these structural changes may not correspond to any functional changes in visual fields or RNFL thickness.

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“…This study suggests that genetic screening for MYOC mutations should be targeted toward cases with familial rather than sporadically occurring JOAG. Criscione et al [16] identified a novel MYOC variant (c.1153G>A) in a Hispanic patient with JOAG. Further genetic testing within her family demonstrated that the variant segregates with JOAG in an autosomal dominant pattern, implying its pathogenicity.…”

Section: Geneticsmentioning

confidence: 99%

Juvenile open angle glaucoma: current diagnosis and management

Ciociola¹,

Klifto

2021

Current Opinion in Ophthalmology

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Purpose of reviewThe aim of this article is to summarize up-to-date research on the diagnosis and management of juvenile open-angle glaucoma (JOAG). Recent findingsJOAG can be subclassified into four clinical phenotypes, and faster myopic shift is a risk factor for disease progression. Vessel density is associated with structural damage and worsening visual acuity in JOAG and can be monitored with optical coherence tomography angiography. Genetic studies have revealed molecular causes of JOAG including variants in CPAMD8, MYOC, and CYP1B1. Tube shunt surgeries as well as gonioscopy-assisted transluminal trabeculotomy have been shown to be successful in JOAG. SummaryAlthough genetic advances may improve future screening, intraocular pressure monitoring and fundoscopic exam remain the current mainstay of diagnosis. Medical treatment alone for JOAG is typically insufficient with patients requiring surgical management. Selective laser trabeculoplasty may delay or decrease the need for surgery. Trabeculectomy has traditionally been shown to be effective in JOAG, but tube shunt surgery and microinvasive glaucoma surgery are effective alternatives.

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Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure

Cited by 7 publications

References 30 publications

Genetic changes and testing associated with childhood glaucoma: A systematic review

Genetic changes and testing associated with childhood glaucoma: A systematic review

Case Report: Reversal and subsequent return of optic disc cupping in a myocilin (MYOC) gene-associated severe Juvenile Open-Angle Glaucoma (JOAG) patient

Juvenile open angle glaucoma: current diagnosis and management

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