Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Open Access

Peer-reviewed

Research Article

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

  • Anika Kumar,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing

    Affiliation Department of Ophthalmology, University of California San Francisco, San Francisco, California, United States of America

    ⨯
  • Ying Han,

    Roles Investigation, Writing – review & editing

    Affiliation Department of Ophthalmology, University of California San Francisco, San Francisco, California, United States of America

    ⨯
  • Julius T. Oatts

    Roles Conceptualization, Data curation, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing

    julius.oatts@ucsf.edu

    Affiliation Department of Ophthalmology, University of California San Francisco, San Francisco, California, United States of America

    ⨯

Abstract

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.

Citation: Kumar A, Han Y, Oatts JT (2024) Genetic changes and testing associated with childhood glaucoma: A systematic review. PLoS ONE 19(2): e0298883. https://doi.org/10.1371/journal.pone.0298883

Editor: Petros C. Cyrus Kayange, Kamuzu University of Health Sciences, MALAWI

Received: December 12, 2023; Accepted: January 30, 2024; Published: February 22, 2024

Copyright: © 2024 Kumar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: JTO received funding from the National Eye Institute/National Institutes of Health (NEI/NIH K23EY034893, NEI/NIH EY002162 Core Grant for Vision Research, https://www.nei.nih.gov/). The funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Glaucoma in children is a rare but potentially visually devastating condition characterized by elevated intraocular pressure, optic nerve damage, and the potential to cause irreversible blindness if not diagnosed and treated in a timely manner [1]. Childhood glaucoma is typically diagnosed clinically on the basis of intraocular pressure elevation, signs of glaucomatous optic nerve damage, corneal changes, or visual field defects consistent with glaucomatous optic nerve damage [2]. In some cases, genetic testing can establish a molecular diagnosis as many forms of childhood glaucoma, including primary congenital glaucoma (PCG), juvenile open angle glaucoma (JOAG), and glaucoma associated with non-acquired ocular or systemic diseases, have been associated with underlying genetic changes [3]. Understanding these genetic changes has the potential to shed light on pathophysiologic mechanisms of disease, disease prognostication, and treatment implications.

Currently, various clinical practice guidelines recommend that children at high risk of developing glaucoma should undergo an eye examination to detect disease [4–6]. Even though many genes have been implicated in the childhood glaucoma [7–9], no current guidelines outline specific protocols for populations who may be genetically “at increased risk.” Additionally, for children with a confirmed diagnosis of glaucoma, the frequency and type of genetic testing is variable. This may be driven by the relative nascency of childhood glaucoma genetics that has not yet resulted in enough centralized high quality evidence to influence standard clinical practice, or the fact that genetic testing associated with childhood glaucoma can be inconsistent or inconclusive [10, 11]. This study summarizes the current body of evidence evaluating genetic changes and testing associated with childhood glaucoma.

Materials and methods

Inclusion and exclusion criteria

Studies were included in the systematic review if (1) they were prospective or retrospective cohort studies, cross-sectional studies, case-control studies, case series, or case reports, and (2) they specifically discussed genetic changes or testing associated with primary congenital glaucoma, juvenile-onset open angle glaucoma, secondary glaucoma associated with congenital non-acquired ocular anomalies, or unspecified glaucoma with age of onset between 0–18 years. Articles were excluded if (1) they were review articles, letters, or abstract-only publications (2) they discussed genetic changes or testing related to syndromic glaucoma with systemic features, (3) they lacked a child-specific analysis or discussion, or (4) they were not available as full-text articles in English.

Search strategy

To ensure a comprehensive review of the available literature, Pubmed, Embase, and Cochrane databases were all queried using the following 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). Additionally, relevant citations from papers identified through these databases were manually identified. All relevant studies published on or before March 2, 2023 were included.

Study selection and data collection.

After searching the databases, all titles and abstracts were screened by a single reviewer (AK) to exclude irrelevant studies. Full text review was subsequently conducted in accordance with the aforementioned inclusion and exclusion criteria. Data was then extracted for all studies that met criteria by a single reviewer (AK). Data extracted included year of study, study design, sample size, mean age and sex breakdown of study population, etiology of glaucoma included in study, genes or genetic tests studied, specific genetic changes identified, and any quantitative measures reported in the study, such as diagnostic yield, prevalence of genetic changes, and genotype-phenotype correlations. An independent validation of both the screening and data extraction process on a random 20% sample was conducted by a second reviewer (JO).

Risk of bias assessment

A risk of bias assessment was then performed independently using the Newcastle-Ottawa Scale tool for cohort and case-control studies [12], as well as modified instruments for cross-sectional studies [13] and case reports and series [14], by two investigators (AK and JO). Disagreements were adjudicated by a third party (YH).

Data synthesis and analysis

Results across studies were summarized using Microsoft Excel Version 16.0 (Redmond, WA) to provide descriptive statistics, including means and standard deviations of study population sizes and ages. This study did not require review by the Institutional Review Board because no patient data were included. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) 2020 updated guidelines for reporting systematic reviews [15]. PRISMA checklist in S1 Checklist, Additionally, the methodological protocol of the search was registered with Prospero in February 2023 (ID CRD42023400467). Protocol in S1 Protocol.

Study characteristics

Systematic search of the Pubmed, Embase, and Cochrane databases resulted in the identification of 2,349 studies published as of March 2, 2023. Following the removal of duplicates, 1,916 articles remained (Fig 1). Following exclusion of 1,255 of those studies based on screening of abstracts and titles alone, the remaining 661 studies underwent full-text review. Of those, 305 were excluded on the basis of relevance, 70 were excluded for being non-pediatric studies, 72 were excluded on the basis of study design, and 18 were excluded for not being available as full-texts in English. Following this assessment for eligibility, 196 studies were eligible for inclusion in the systematic review. A complete spreadsheet containing all data fields extracted from included studies can be found in S1 Appendix.

thumbnail
Download:
Fig 1. PRISMA flow diagram.

https://doi.org/10.1371/journal.pone.0298883.g001

Of the 196 included studies, 36 (18.4%) were case reports, 40 (20.4%) were case series, 15 (7.7%) were case-control studies, 91 (66.9%) were cross-sectional studies, 7 (3.6%) were prospective cohort studies, and 7 (3.6%) were retrospective cohort studies. Twenty-three of the studies (11.7%) were published between 1993 and 2002, 58 (29.6%) between 2003 and 2012, and 115 (58.7%) between 2013 and March 2023. Within the studies, 53 unique genes were discussed. The most common gene discussed in the studies was CYP1B1, evaluated in 109 (55.6%) of the studies, followed by MYOC in 31 (15.8%), and FOXC1 in 25 (12.8%). Of the included studies that were not case reports, mean±SD number of study participants was 80.3±139.4 participants. The total number of participants included across all 196 studies was 12,607. Of the studies that published data on participant age, mean age±SD at glaucoma diagnosis was 8.94±9.54 years. Of the studies that published data on participant sex, an average of 50.4% were male. A comprehensive list of all genes, proposed functions, and glaucoma associations is shown in Table 1.

thumbnail
Download:
Table 1. Nuclear genes associated with childhood glaucoma in published literature.

https://doi.org/10.1371/journal.pone.0298883.t001

Overall, risk of bias was low among included studies. Of the case reports and series, 80% scored a 4 or higher out of 5 on the modified Newcastle-Ottawa scale for case series and reports, with the most common domain for bias being selection. Of the case-control studies, 70% scored a 6 or higher out of 9 on the Newcastle-Ottawa scale for case-control studies, with the most common domain for bias being comparability between cases and controls. Of the cross-sectional studies, 70% scored an 8 or higher out of 10 on the modified Newcastle-Ottawa scale for cross-sectional studies, with the most common domain for bias being comparability between different outcome groups. Of the cohort studies, 100% scored a 6 or higher out of 9 on the Newcastle-Ottawa scale for cohort studies, with the most common domain of bias being selection.

Limitations

This systematic review is limited in that reported summary estimates may have been subject to publication bias; it is possible that reported metrics, such as diagnostic yield or magnitude of genotype-phenotype correlations, may be overestimates of true estimates due to the tendency for positive findings to be overrepresented in the literature. Additionally, this review only included studies that had full text available in the English language, which may have resulted in incomplete summarizations of genetic changes and prevalence estimates by omitting studies in other languages conducted in globally diverse patient populations. Finally, though a comprehensive search strategy was implemented, it is possible that some relevant studies were not included due to variations in terminology or our use of only three major databases.

Discussion/Summary of evidence

CYP1B1

The CYP1B1 gene, which encodes a cytochrome P450 family protein and is highly expressed in the eye, is arguably one of the most investigated genomic regions in the setting of childhood glaucoma. In PCG, CYP1B1 variants are thought to be related to impaired metabolism of retinol, which disrupts retinoic acid levels required for ocular development [43]. Its increased expression in fetal eyes as compared to adult eyes suggests its significance in the development of childhood glaucoma specifically [190]. Numerous case reports have highlighted the incidence of bilateral PCG in those with homozygous or compound heterozygous CYP1B1 variants in individuals both with and without a family history of the disease, with the most common variants being p.G61E, p.R368H, pE229K, and p.R390H [26–36].

Of analytical studies investigating the prevalence of genetic changes associated with childhood glaucoma, CYP1B1 variants are the most common with varying prevalence across regions and populations. For example, among patients with PCG, cross-sectional studies have found the prevalence of CYP1B1 variants to range between 5% and 23% in South Africa [71], China [46, 62], America [68], Vietnam [54], Japan [69, 94, 104, 107], and Germany [24], while prevalences range from 30% to 55% in studies from India [79, 95], Turkey [72, 98], Portugal [57, 128], Morocco [40], Spain [118], and France [103]. Among PCG patients, CYP1B1 variants appear to be most prevalent in some South Asian and Middle Eastern populations as prevalences have been found to range from 64% to 85.7% in studies from Pakistan [99], Iran [63], and Saudi Arabia [47, 113, 123]. Prevalence of specific variants has also been found to be region- and population-specific. For example, among PCG patients, the prevalence of the missense p.G61E variant was found to be 7.8% in a Moroccan population [114], 47.1% in an Iranian population [119], 50% in an Israeli Bedouin population [49], and 63% in a Saudi Arabian population [66]. Additionally, while the frequency of the missense p.E378K variant was only 6.67% in a Mexican population [50], it was 100% in a Slovak population of patients with PCG, indicating a potential founder effect [77]. Studies have also evaluated the prevalence of CYP1B1 variants in patients with various ocular anomalies. For example, the prevalence was found to be as high as 91% in patients with buphthalmos, including ectropion uveae and partial aniridia [87], 92.3% in patients with ectropion uveae [100], and 0% in patients with the Axenfeld-Rieger anomaly [117]. Together, this research highlights the relative prevalence of CYP1B1 variants among cases of childhood glaucoma and also suggests that testing for such variants has varying degrees of utility depending on the patient population and ocular manifestations.

In evaluating genotype-phenotype correlations, studies have shown that those with homozygous CYP1B1 variants generally display more severe clinical phenotypes compared to those without. For example, variants in CYP1B1 have been associated with earlier age of disease onset [57, 75, 106, 191], higher likelihood of developing bilateral disease [57, 64, 75], higher intraocular pressure [64, 106], and requirement of more medical and surgical interventions [58, 75, 113]. However, among patients with CYP1B1 genetic changes, penetrance is not full, and phenotypic severity has been found to be variable, suggesting the presence of some type of genetic modification through interaction with other genes [89]. Several studies have explored whether the type of CYP1B1 variant affects the phenotype. For example, in West Siberia, variants in codon 444 were associated with the most severe phenotypes, suggesting that codon’s role in structural stabilization of the resulting protein [115]. Additionally, null variants have been found to be associated with a need for greater number of surgeries and earlier age of disease onset [33, 67]. In another study, the percentage of PCG patients with “severe” phenotypes was 100% in those with frameshift variants, 80% with missense p.E229K variants, and 66.7% with missense p.G61E variants [52]. However, in some familial studies, phenotypes of different degrees of severity have been observed among patients with the exact same variant, even within the same family, demonstrating that variant alone cannot account for all phenotypic differences [45, 121]. Overall, future studies investigating the effect of CYP1B1 variants in both functional protein models and human correlates will be essential in predicting disease course and phenotypic severity of those with variants.

FOXC1 and PITX2

The FOXC1 gene encodes the forkhead box C1 protein, which is a transcription factor foundational in the regulation of embryonic and ocular development and highly expressed in important ocular structures including the iris, cornea, and trabecular meshwork [192]. Many case reports have described a spectrum of conditions associated with variants in this gene, most commonly including the Axenfeld-Rieger anomaly, as well as aniridia and megalocornea in the setting of heterozygous FOXC1 variants [132–136]. Frequently reported variants associated with varying degrees of phenotypic severity in case series include missense variants of the arginine residue at position 127 [129, 138, 146], deletions [48, 137, 142], and duplications [139]. Among cross-sectional studies in German, Australian, Italian, and Spanish populations of patients with PCG and glaucoma associated with non-acquired ocular anomalies, the prevalence of FOXC1 variants appears to range between 4% and 7.5% [24, 25, 143–145]. Through functional protein analysis, it has been proposed that a dose-dependent relationship exists between FOXC1 expression and phenotype where variants that result in 50–60% or 130–150% of transcriptional activity are associated with glaucoma, and activity beyond these levels result in more severe anterior segment anomalies and extraocular manifestations [141]. For example, in one study of Swiss families, it was found that those with duplications with hypothesized 150% transcriptional activity exhibited glaucoma with less phenotypic severity than those with a frameshift FOXC1 variants that resulted in little to no transcriptional activity [128]. Overall, these studies demonstrate a significant amount of phenotypic heterogeneity associated with relatively prevalent changes in FOXC1 and future research is required to delineate the hypomorphic and hypermorphic variants associated with the most severe phenotypes.

Of note, the FOXC1 gene has significant functional interactions with the PITX2 gene, another gene implicated in childhood glaucoma [193]. The PITX2 gene encodes the paired-like homeodomain 2 protein, a transcription factor involved in negative regulation of the FOXC1 gene. Loss of function PITX2 variants result in inappropriately extensive activation of FOXC1-target genes [194]. Thus, variants in PITX2 have been reported in glaucoma associated with Axenfeld-Rieger syndrome even in the absence of FOXC1 variants [17, 184]. Though FOXC1 and PITX2 variants are thought to cause childhood glaucoma through a similar mechanism, studies have shown that FOXC1 variants (as compared to PITX2 variants) have significantly greater disease penetrance and earlier age of onset [147, 148]. However, one study observed that despite increased prevalence of disease at age 10 in those with FOXC1 variants as compared to PITX2 variants, difference in prevalence was no longer significant at age 25 [140]. Additionally, FOXC1 variants are potentially more likely to be associated with corneal abnormalities and need for glaucoma surgery than PITX2 variants [148]. Overall, these studies highlight that identification of causative genes in patients with Axenfeld-Rieger syndrome may have implications in anticipating phenotypic severity, disease progression, and surgical intervention requirements; future research is required to particularize these relationships with age.

LTBP2

The LTBP2 gene encodes the latent transforming growth factor beta binding protein 2, an extracellular matrix protein thought to be essential in ciliary microfibril development and the development of correct lens placement and suspension. It is located within 1.5 Mb from the GLC3 locus, which has been linked to PCG in family linkage studies [7]. LTBP2 variants have also been described in association with microspherophakia, megalocornea, and ectopia lentis: all non-acquired ocular anomalies that can co-exist with glaucoma. For example, reports have described compound heterozygous LTBP2 variants and the coexistence of LTBP2 variants in those with MYOC variants contributing to severe childhood glaucomatous phenotypes [155, 195]. Additionally, some familial observational case series have described missense and frameshift variants in Iranian and Pakistani pedigrees, noting that consanguinity was present in all studied families [150–152]. The prevalence of LTBP2 variants in childhood glaucoma patients is population-specific. For example, no variants to date have been identified in cross-sectional studies of PCG and JOAG populations from China, South Africa, Saudi Arabia, or the United States [68, 71, 123, 153]. However, LTBP2 variants have been identified in 4–5.6% of study participants with childhood glaucoma in Germany [24, 25] and 12.5% in India [44]. Additionally, a single p.R299X variant has been identified in 40.5% of patients with PCG that all originated from the Roma founder population, with homozygotes for the variant presenting with more severe ocular phenotypes than heterozygotes [82]. Collectively, these findings suggest that the prevalence of causal LTBP2 variants may be region-specific, and that using LTBP2 sequencing for molecular diagnosis may not be productive in certain populations. Future research examining the association between LTBP2 variant prevalence and consanguinity in a variety of different locations will help elucidate populations in which LTBP2 testing may be the most valuable.

MYOC

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]. In cross-sectional analyses, the prevalence of MYOC variants has been found to range between 2.3% and 2.6% in Chinese and Indian populations with PCG [53, 166]. The prevalence in patients with JOAG is higher and has been found to range between 4% and 36% among Iranian, Canadian, Spanish, American, and Chinese populations [9, 118, 122, 161, 166]. Additionally, a study of the age-based prevalence of MYOC variants found that MYOC variants were identified in 36% of American glaucomatous probands with juvenile-onset disease as compared to only 4% of probands with adult-onset disease [161]. Together, these studies demonstrate that screening for MYOC variants is of highest utility in patients with JOAG or members of families with history of early-onset glaucoma.

MYOC variants have also been found to have significant interactions with other genes implicated in childhood glaucoma. For example, one study found that patients with coexisting MYOC and OPTN variants had more severe ocular phenotypes than those with MYOC variants alone [164]. The OPTN gene codes for the optineurin protein, which is expressed during early stages of eye development and helps regulate cellular functions such as protein trafficking and NF-κB pathway maintenance in the trabecular meshwork and retina. Though this phenomenon has not been extensively characterized in humans, cellular studies have noted that OPTN upregulation results in increased stability of MYOC mRNA; thus, loss of function variants at the OPTN gene drive dysregulation of MYOC expression [197], providing a possible pathophysiological mechanism of their interaction. Another study found that those with concurrent MYOC and CYP1B1 variants had a much earlier age of onset of disease than those with MYOC variants alone [9]. One hypothesis for this interaction is that the CYP1B1 protein may be involved in metabolism of endogenous steroids, which are known to induce the myocilin protein; thus metabolic derangements from CYP1B1 variants may further exacerbate the ramifications of any mutant myocilin proteins [198, 199]. Overall, the role of multiple genes in potential modification of MYOC gene expression implies a common interaction pathway. Further studies of functional protein interactions and their resulting clinical manifestations will be useful in understanding the mechanisms by which MYOC variants contribute to glaucoma and which patients may be at risk for developing the most severe phenotypes.

TEK

The TEK gene encodes the tunica interna endothelial cell kinase, which is a tyrosine kinase protein that mediates embryonic vascular development through angiopoietin signaling [37]. Though its exact function in the development of glaucoma remains unknown, TEK variants are thought to impair aqueous humor outflow and Schlemm’s canal development [200]. Though no specific variants appear to be predominant among TEK variants described in the literature, estimates of the prevalence of TEK variants in general range from 4% to 5.9% among German, Chinese, Australian, and South African populations with PCG, JOAG, and glaucoma associated with non-acquired ocular anomalies [18, 24, 25, 71, 187]. Unlike other genetic changes associated with childhood glaucoma, studies have demonstrated that the phenotypic penetrance of TEK variants is relatively low. For example, in one study of TEK variants in Australian patients with early-onset glaucoma, only 75% of those with TEK variants exhibited bilateral glaucoma, as compared to at least 97% of those with CYP1B1, LTBP2, and MYOC variants, for example [18]. In another study of PCG in Chinese patients, penetrance was only 68.5% [187]. It is worth mentioning that these studies were limited in that they did not investigate the association between penetrance and type of variant in large sample sizes; thus, it is possible that a dose-dependent or protein-structure effect, or other relationship, exists between TEK gene expression and phenotype that has yet to be identified. Regardless, one possible explanation is that TEK gene expression is highly susceptible to the influence of interaction with other genes. For example, one study has proposed that the SVEP1 gene could be a potent genetic modifier as SVEP1 loss of function alleles were demonstrated to reduce TEK expression in vascular endothelial cells in animal models and correlate with increased disease severity in human families with PCG [186]. The SVEP1 gene encodes an extracellular matrix glycoprotein involved in epidermal and lymph vessel development. Another study identified the coexistence of heterozygous TEK and CYP1B1 variants in cases of PCG; they then conducted functional analyses demonstrating that recombinant CYP1B1 proteins interacted with recombinant TEK proteins to decrease TEK signaling [37]. Further studies evaluating modulators of this gene’s expressivity can help elucidate the pathophysiological mechanism by which it drives glaucoma and help predict which patients with TEK variants may be at greatest risk of severe disease.

Real world genetic testing practice

Though no standard guidelines exist regarding genetic testing for childhood glaucoma, several studies have investigated its use in the real world. For example, in a cross-sectional study of pediatric referral practices in India, patients with glaucoma and objective features suggesting an underlying genetic abnormality were less than half as likely to be referred for formal genetic evaluation when they met with ophthalmologists than when they met with geneticists [201]. Though these findings may not be generalizable to all provider practices, it suggests that in general, there is room to improve initiating genetic testing. One potential explanation for this may relate to providers’ hesitation around the utility of testing relative to the potential financial and logistical expenditures. A study investigating the diagnostic yield of genetic testing of early-onset glaucoma patients in a real world practice setting found that next generation sequencing was able to identify a causative variant in only 19% of those tested [202]. Notably, diagnostic yield was 32% in patients with glaucoma onset before 3 years of age but only 5% in patients with onset after three years of age, suggesting more limited utility of testing for later onset glaucoma. Additionally, in a study of 39 patients with PCG referred to a pediatric ocular genetics service in England, diagnostic yield of whole exome sequencing was only 12.8% [203]. In another study of 28 preschool-aged probands with anterior segment dysgenesis, including glaucoma, diagnostic yield was 39%. Additionally, it was found that establishing a molecular diagnosis altered management in 18% of those patients through avoidance of additional unnecessary tests and initiation of surveillance for other extraocular manifestations [204]. The lack of consistent recommendations for genetic testing may also relate to other practical barriers to incorporation of genetics assessments into clinical practice, including shortages of qualified ophthalmic genetic counselors, which can result in long wait times for patients to be evaluated [205]. Overall, while existing research demonstrates promising data on the utility of real world genetic testing, especially in patients with earlier onset glaucoma, future research on its capability to inform disease management is necessary to help shape provider practice patterns.

Conclusion

Numerous genes and genetic changes have been described in association with childhood glaucoma, with the most common being CYP1B1, MYOC, and FOXC1. There is significant variability in genotype-phenotype correlation based on the specific gene and variant identified. Studies of real world genetic testing reveal a relatively low diagnostic yield, which may limit the practicality of genetic testing with currently available tools. Understanding the underlying genetic changes associated with childhood glaucoma has the potential to improve diagnostic, prognostic, and potentially therapeutic outcomes for children with glaucoma.

Supporting information

S1 Checklist. Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) checklist.

https://doi.org/10.1371/journal.pone.0298883.s001

(PDF)

S1 Protocol. Prospero protocol.

https://doi.org/10.1371/journal.pone.0298883.s002

(PDF)

S1 Appendix. Complete extracted characteristics from included studies.

https://doi.org/10.1371/journal.pone.0298883.s003

(XLSX)

References

  1. 1. Fung DS, Roensch MA, Kooner KS, Cavanagh HD, Whitson JT. Epidemiology and characteristics of childhood glaucoma: results from the Dallas Glaucoma Registry. Clin Ophthalmol Auckl NZ. 2013;7:1739–46. pmid:24039394
  2. 2. Thau A, Lloyd M, Freedman S, Beck A, Grajewski A, Levin AV. New classification system for pediatric glaucoma: implications for clinical care and a research registry. Curr Opin Ophthalmol. 2018 Sep;29(5):385–94. pmid:30096087
  3. 3. Karaconji T, Zagora S, Grigg JR. Approach to childhood glaucoma: A review. Clin Experiment Ophthalmol. 2022 Mar;50(2):232–46. pmid:35023613
  4. 4. National Health and Medical Research Council. Guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma. 2010;
  5. 5. Wallace DK, Morse CL, Melia M, Sprunger DT, Repka MX, Lee KA, et al. Pediatric Eye Evaluations Preferred Practice Pattern®. Ophthalmology. 2018 Jan;125(1):P184–227.
  6. 6. AOA Evidence-Based Optometry Guideline Development Group. Comprehensive pediatric eye and vision examination. Am Optom Assoc. 2017;
    • 7. Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, et al. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664–71. pmid:19361779
    • 8. Souma T, Tompson SW, Thomson BR, Siggs OM, Kizhatil K, Yamaguchi S, et al. Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J Clin Invest. 2016 Jul 1;126(7):2575–87. pmid:27270174
    • 9. Vincent AL, Billingsley G, Buys Y, Levin AV, Priston M, Trope G, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet. 2002 Feb;70(2):448–60. pmid:11774072
    • 10. Abdolrahimzadeh S, Fameli V, Mollo R, Contestabile MT, Perdicchi A, Recupero SM. Rare Diseases Leading to Childhood Glaucoma: Epidemiology, Pathophysiogenesis, and Management. BioMed Res Int. 2015;2015:781294. pmid:26451378
    • 11. Lingham G, Thakur S, Safi S, Gordon I, Evans JR, Keel S. A systematic review of clinical practice guidelines for childhood glaucoma. BMJ Open Ophthalmol. 2022;7(1):e000933. pmid:35136841
    • 12. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013; Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
    • 13. Ribeiro CM, Beserra BTS, Silva NG, Lima CL, Rocha PRS, Coelho MS, et al. Exposure to endocrine-disrupting chemicals and anthropometric measures of obesity: a systematic review and meta-analysis. BMJ Open. 2020 Jun;10(6):e033509. pmid:32565448
    • 14. Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid-Based Med. 2018 Apr;23(2):60–3. pmid:29420178
    • 15. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;n71.
    • 16. Jakobsson C, El-Haig W, Abouzeid H, Schorderet DF. Novel ADAM9 mutation in a consanguineous Egyptian family with severe Cone-Rod Dystrophy. Invest Ophthalmol Vis Sci. 2014;55(13):3277.
    • 17. Titheradge H, Togneri F, McMullan D, Brueton L, Lim D, Williams D. Axenfeld-Rieger syndrome: further clinical and array delineation of four unrelated patients with a 4q25 microdeletion. Am J Med Genet A. 2014 Jul;164A(7):1695–701. pmid:24715413
    • 18. Knight LSW, Ruddle JB, Taranath DA, Goldberg I, Smith JEH, Gole G, et al. Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry. Ophthalmology. 2021 Nov;128(11):1549–60. pmid:33892047
    • 19. Casalino G, Khan KN, Armengol M, Wright G, Pontikos N, Georgiou M, et al. Autosomal Recessive Bestrophinopathy: Clinical Features, Natural History, and Genetic Findings in Preparation for Clinical Trials. Ophthalmology. 2021;128(5):706–18. pmid:33039401
    • 20. Gupta V, Panigrahi A, Mahalingam K, Singh A, Somarajan BI, Gupta S. Expanding the phenotypic spectrum of CYP1B1 associated primary congenital glaucoma. Clin Experiment Ophthalmol. 2022 Dec;50(9):1112–5. pmid:36076309
    • 21. Siggs OM, Souzeau E, Taranath DA, Dubowsky A, Chappell A, Zhou T, et al. Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma. Ophthalmology. 2020 Jun;127(6):758–66. pmid:32085876
    • 22. Bonet Fernandez JMM, Aroca-Aguilar JD, García-Antón MT, Ramírez AI, Alexandre-Moreno S, Salazar JJ, et al. CPAMD8 loss-of-function in a family with non-dominant congenital glaucoma and anterior segment dysgenesis. Invest Ophthalmol Vis Sci [Internet]. 2020;61(7). Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L632698391&from=export
    • 23. Wiggs JL. Ophthalmology. 2020 Jun;127(6):767–8.
    • 24. Aghayeva FA, Schuster AK, Diel H, Chronopoulos P, Wagner FM, Grehn F, et al. Childhood glaucoma registry in Germany: initial database, clinical care and research (pilot study). BMC Res Notes. 2022 Feb 10;15(1):32. pmid:35144644
    • 25. Stingl JV, Diederich S, Diel H, Schuster AK, Wagner FM, Chronopoulos P, et al. First Results from the Prospective German Registry for Childhood Glaucoma: Phenotype-Genotype Association. J Clin Med. 2021 Dec 21;11(1):16. pmid:35011756
    • 26. Kakiuchi T, Isashiki Y, Nakao K, Sonoda S, Kimura K, Ohba N. A novel truncating mutation of cytochrome P4501B1 (CYP1B1) gene in primary infantile glaucoma. Am J Ophthalmol. 1999 Sep;128(3):370–2. pmid:10511040
    • 27. Lombardo B, Ceglia C, Tarsitano M, Pastore L. CGH array for the identification of a compound heterozygous mutation in CYP1B1 gene in a patient with a suspect primary congenital glaucoma. Biochim Clin. 2013;37((Lombardo B.; Pastore L.) Biochimica e Biotecnologie Mediche, Università Degli Studi di Napoli “Federico II,” Italy):S121.
    • 28. Khan AO, Aldahmesh MA, Mohamed JY, Hijazi H, Alkuraya FS. Complete aniridia with central keratopathy and congenital glaucoma is a CYP1B1-related phenotype. Ophthalmic Genet. 2014 Sep;35(3):187–9. pmid:23767995
    • 29. Bashir R, Tahir H, Yousaf K, Naz S, Naz S. Homozygous p.G61E mutation in a consanguineous Pakistani family with co-existence of juvenile-onset open angle glaucoma and primary congenital glaucoma. Gene. 2015 Oct 10;570(2):295–8. pmid:26164761
    • 30. Zavarzadeh PG, Bonyadi M, Abedi Z. Whole-exome sequencing analysis in a case of primary congenital glaucoma due to the partial uniparental isodisomy. Genomics Inform. 2022 Sep;20(3):e28. pmid:36239105
    • 31. Talebi F, Mardasi FG, Asl JM, Lashgari A. Mutational spectrum of the CYP1B1 gene in Iranain primary congenital glaucoma family. Can J Ophthalmol J Can Ophtalmol. 2018 Jun;53(3):e87–9. pmid:29784182
    • 32. Cai S, Zhang D, Jiao X, Wang T, Fan M, Wang Y, et al. Novel compound heterozygous mutations in CYP1B1 identified in a Chinese family with developmental glaucoma. Mol Med Rep. 2021 Nov;24(5):803. pmid:34528698
    • 33. López-Garrido MP, Campos-Mollo E, Harto MA, Escribano J. Primary congenital glaucoma caused by the homozygous F261L CYP1B1 mutation and paternal isodisomy of chromosome 2. Clin Genet. 2009 Dec;76(6):552–7. pmid:19807744
    • 34. Souzeau E, Dubowsky A, Ruddle JB, Craig JE. Primary congenital glaucoma due to paternal uniparental isodisomy of chromosome 2 and CYP1B1 deletion. Mol Genet Genomic Med. 2019 Aug;7(8):e774. pmid:31251480
    • 35. Salehi Chaleshtori AR, Garshasbi M, Salehi A, Noruzinia M. The Identification and Stereochemistry Analysis of a Novel Mutation p.(D367Tfs*61) in the CYP1B1 Gene: A Case Report. J Curr Ophthalmol. 2020;32(1):114–8. pmid:32510024
    • 36. Safari I, Suri F, Haji-Seyed-Javadi R, Yazdani S, Elahi E. The p.Gly61Glu Mutation in CYP1B1 Affects the Extracellular Matrix in Glaucoma Patients. Ophthalmic Res. 2016 Jul;56(2):98–103. pmid:26982174
    • 37. Kabra M, Zhang W, Rathi S, Mandal AK, Senthil S, Pyatla G, et al. Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma. Hum Genet. 2017 Aug;136(8):941–9. pmid:28620713
    • 38. Ferre-Fernández JJ, Aroca-Aguilar JD, Méndez-Hernández CD, Fernandez-Vidal A, García Feijoo J, Escribano J. Identifying genes involved in primary congenital glaucoma using whole exome sequencing. Ophthalmic Res. 2013;50(1):48.
    • 39. Alzuhairy S, Abu-Amero KK, Al-Shahwan S, Edward DP. A novel CYP1B1 mutation with congenital glaucoma and total aniridia. Ophthalmic Genet. 2015 Mar;36(1):89–91. pmid:24001018
    • 40. Belmouden A, Melki R, Hamdani M, Zaghloul K, Amraoui A, Nadifi S, et al. A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco. Clin Genet. 2002 Oct;62(4):334–9. pmid:12372064
    • 41. Chakrabarti S, Ghanekar Y, Kaur K, Kaur I, Mandal AK, Rao KN, et al. A polymorphism in the CYP1B1 promoter is functionally associated with primary congenital glaucoma. Hum Mol Genet. 2010 Oct 15;19(20):4083–90. pmid:20660114
    • 42. Rauf B, Irum B, Kabir F, Firasat S, Naeem MA, Khan SN, et al. A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent. Hum Genome Var. 2016;3:16021. pmid:27508083
    • 43. Reis LM, Tyler RC, Weh E, Hendee KE, Kariminejad A, Abdul-Rahman O, et al. Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes. Mol Vis. 2016;22:1229–38. pmid:27777502
    • 44. Yang Y, Zhang L, Li S, Zhu X, Sundaresan P. Candidate Gene Analysis Identifies Mutations in CYP1B1 and LTBP2 in Indian Families with Primary Congenital Glaucoma. Genet Test Mol Biomark. 2017 Apr;21(4):252–8. pmid:28384041
    • 45. Bashir R, Yousaf K, Tahir H, Sanai M, Qayyum S, Naz S, et al. Clinical variability of CYP1B1 gene variants in Pakistani primary congenital glaucoma families. JPMA J Pak Med Assoc. 2018 Aug;68(8):1205–11. pmid:30108387
    • 46. Song N, Leng L, Yang XJ, Zhang YQ, Tang C, Chen WS, et al. Compound heterozygous mutations in CYP1B1 gene leads to severe primary congenital glaucoma phenotype. Int J Ophthalmol. 2019;12(6):909–14. pmid:31236345
    • 47. Alsaif HS, Khan AO, Patel N, Alkuraya H, Hashem M, Abdulwahab F, et al. Congenital glaucoma and CYP1B1: an old story revisited. Hum Genet. 2019 Sep;138(8–9):1043–9. pmid:29556725
    • 48. Khan AO, Aldahmesh MA, Mohamed JY, Alkuraya FS. Congenital glaucoma with acquired peripheral circumferential iris degeneration. J AAPOS Off Publ Am Assoc Pediatr Ophthalmol Strabismus. 2013 Feb;17(1):105–7. pmid:23363883
    • 49. Bar-Yosef U, Levy J, Elbedour K, Ofir R, Carmi R, Birk OS. Congenital glaucoma: CYP1B1 mutations in Israeli Bedouin kindreds. J Glaucoma. 2010 Jan;19(1):35–8. pmid:19593207
    • 50. Zenteno JC, Hernandez-Merino E, Mejia-Lopez H, Matías-Florentino M, Michel N, Elizondo-Olascoaga C, et al. Contribution of CYP1B1 mutations and founder effect to primary congenital glaucoma in Mexico. J Glaucoma. 2008;17(3):189–92. pmid:18414103
    • 51. Bashir R, Sanai M, Azeem A, Altaf I, Saleem F, Naz S. Contribution of GLC3A locus to Primary Congenital Glaucoma in Pakistani population. Pak J Med Sci. 2014;30(6):1341–5. pmid:25674135
    • 52. Panicker SG, Mandal AK, Reddy ABM, Gothwal VK, Hasnain SE. Correlations of genotype with phenotype in Indian patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1149–56. pmid:15037581
    • 53. Chen Y, Jiang D, Yu L, Katz B, Zhang K, Wan B, et al. CYP1B1 and MYOC mutations in 116 Chinese patients with primary congenital glaucoma. Arch Ophthalmol Chic Ill 1960. 2008 Oct;126(10):1443–7. pmid:18852424
    • 54. Do T, Shei W, Chau PTM, Trang DL, Yong VHK, Ng XY, et al. CYP1B1 and MYOC Mutations in Vietnamese Primary Congenital Glaucoma Patients. J Glaucoma. 2016 May;25(5):e491–498. pmid:26550974
    • 55. Kaushik S, Luthra-Guptasarma M, Prasher D, Dhingra D, Singh N, Kumar A, et al. CYP1B1 and MYOC variants in neonatal-onset versus infantile-onset primary congenital glaucoma. Br J Ophthalmol. 2023 Feb;107(2):227–33. pmid:34526297
    • 56. Souzeau E, Hayes M, Ruddle JB, Elder JE, Staffieri SE, Kearns LS, et al. CYP1B1 copy number variation is not a major contributor to primary congenital glaucoma. Mol Vis. 2015;21:160–4. pmid:25750510
    • 57. Cardoso MS, Anjos R, Vieira L, Ferreira C, Xavier A, Brito C. CYP1B1 gene analysis and phenotypic correlation in Portuguese children with primary congenital glaucoma. Eur J Ophthalmol. 2015;25(6):474–7. pmid:25952714
    • 58. Della Paolera M, de Vasconcellos JPC, Umbelino CC, Kasahara N, Rocha MN, Richeti F, et al. CYP1B1 gene analysis in primary congenital glaucoma Brazilian patients: novel mutations and association with poor prognosis. J Glaucoma. 2010 Mar;19(3):176–82. pmid:19528825
    • 59. Sitorus R, Ardjo SM, Lorenz B, Preising M. CYP1B1 gene analysis in primary congenital glaucoma in Indonesian and European patients. J Med Genet. 2003 Jan;40(1):e9. pmid:12525557
    • 60. Coêlho REA, Sena DR, Santa Cruz F, Moura BCFS, Han CC, Andrade FN, et al. CYP1B1 Gene and Phenotypic Correlation in Patients From Northeastern Brazil With Primary Congenital Glaucoma. J Glaucoma. 2019 Feb;28(2):161–4. pmid:30520782
    • 61. Bouyacoub Y, Ben Yahia S, Abroug N, Kahloun R, Kefi R, Khairallah M, et al. CYP1B1 gene mutations causing primary congenital glaucoma in Tunisia. Ann Hum Genet. 2014 Jul;78(4):255–63. pmid:24942078
    • 62. Chen L, Huang L, Zeng A, He J. CYP1B1 gene mutations with incomplete penetrance in a Chinese pedigree with primary congenital glaucoma: a case report and review of literatures. Int J Clin Exp Med. 2015;8(8):14538–41. pmid:26550445
    • 63. Chitsazian F, Tusi BK, Elahi E, Saroei HA, Sanati MH, Yazdani S, et al. CYP1B1 mutation profile of Iranian primary congenital glaucoma patients and associated haplotypes. J Mol Diagn JMD. 2007 Jul;9(3):382–93. pmid:17591938
    • 64. Simões MJ, Carmona S, Roberts R, Wainwright G, Faro C, Silva E, et al. CYP1B1 mutational screening in a Portuguese cohort of primary congenital glaucoma patients. Ophthalmic Genet. 2017;38(2):197–9. pmid:27268095
    • 65. Grønskov K, Redó-Riveiro A, Sandfeld L, Zibrandtsen N, Harris P, Bach-Holm D, et al. CYP1B1 Mutations in Individuals With Primary Congenital Glaucoma and Residing in Denmark. J Glaucoma. 2016 Dec;25(12):926–30. pmid:27820421
    • 66. Badeeb OM, Micheal S, Koenekoop RK, den Hollander AI, Hedrawi MT. CYP1B1 mutations in patients with primary congenital glaucoma from Saudi Arabia. BMC Med Genet. 2014 Sep 28;15:109. pmid:25261878
    • 67. Campos-Mollo E, López-Garrido MP, Blanco-Marchite C, Garcia-Feijoo J, Peralta J, Belmonte-Martínez J, et al. CYP1B1 mutations in Spanish patients with primary congenital glaucoma: phenotypic and functional variability. Mol Vis. 2009;15:417–31. pmid:19234632
    • 68. Lim SH, Tran-Viet KN, Yanovitch TL, Freedman SF, Klemm T, Call W, et al. CYP1B1, MYOC, and LTBP2 mutations in primary congenital glaucoma patients in the United States. Am J Ophthalmol. 2013 Mar;155(3):508–517.e5. pmid:23218701
    • 69. Kakiuchi-Matsumoto T, Isashiki Y, Ohba N, Kimura K, Sonoda S, Unoki K. Cytochrome P450 1B1 gene mutations in Japanese patients with primary congenital glaucoma(1). Am J Ophthalmol. 2001 Mar;131(3):345–50. pmid:11239867
    • 70. Curry SM, Daou AG, Hermanns P, Molinari A, Lewis RA, Bejjani BA. Cytochrome P4501B1 mutations cause only part of primary congenital glaucoma in Ecuador. Ophthalmic Genet. 2004 Mar;25(1):3–9. pmid:15255109
    • 71. Carstens N, Goolam S, Hulley M, Brandenburg JT, Ramsay M, Williams SEI. Exome-based mutation screening in South African children with primary congenital glaucoma. Eye Lond Engl. 2023 Feb;37(2):362–8. pmid:35094026
    • 72. Ava S, Demirtaş AA, Karahan M, Erdem S, Oral D, Keklikçi U. Genetic analysis of patients with primary congenital glaucoma. Int Ophthalmol. 2021 Jul;41(7):2565–74. pmid:33745036
    • 73. Hollander DA, Sarfarazi M, Stoilov I, Wood IS, Fredrick DR, Alvarado JA. Genotype and phenotype correlations in congenital glaucoma: CYP1B1 mutations, goniodysgenesis, and clinical characteristics. Am J Ophthalmol. 2006 Dec;142(6):993–1004. pmid:17157584
    • 74. Geyer O, Wolf A, Levinger E, Harari-Shacham A, Walton DS, Shochat C, et al. Genotype/phenotype correlation in primary congenital glaucoma patients from different ethnic groups of the Israeli population. Am J Ophthalmol. 2011 Feb;151(2):263–271.e1. pmid:21168818
    • 75. Al-Haddad C, Abdulaal M, Badra R, Barikian A, Noureddine B, Farra C. Genotype/Phenotype Correlation in Primary Congenital Glaucoma Patients in the Lebanese Population: A Pilot Study. Ophthalmic Genet. 2016;37(1):31–6. pmid:24940937
    • 76. Narooie-Nejad M, Chitsazian F, Khoramian Tusi B, Mousavi F, Houshmand M, Rohani MR, et al. Genotyping results of Iranian PCG families suggests one or more PCG locus other than GCL3A, GCL3B, and GCL3C exist. Mol Vis. 2009 Oct 22;15:2155–61. pmid:19898634
    • 77. Plásilová M, Stoilov I, Sarfarazi M, Kádasi L, Feráková E, Ferák V. Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma. J Med Genet. 1999 Apr;36(4):290–4. pmid:10227395
    • 78. Tanwar M, Dada T, Sihota R, Dada R. Identification of four novel cytochrome P4501B1 mutations (p.I94X, p.H279D, p.Q340H, and p.K433K) in primary congenital glaucoma patients. Mol Vis. 2009 Dec 30;15:2926–37. pmid:20057908
    • 79. Reddy ABM, Panicker SG, Mandal AK, Hasnain SE, Balasubramanian D. Identification of R368H as a predominant CYP1B1 allele causing primary congenital glaucoma in Indian patients. Invest Ophthalmol Vis Sci. 2003 Oct;44(10):4200–3. pmid:14507861
    • 80. Jubair S, N Al-Rubae’i SH, M Al-Sharifi AN, Jabbar Suleiman AA. Investigation of CYP1B1 Gene Involvement in Primary Congenital Glaucoma in Iraqi Children. Middle East Afr J Ophthalmol. 2019;26(4):203–9. pmid:32153331
    • 81. Yang M, Guo X, Liu X, Shen H, Jia X, Xiao X, et al. Investigation of CYP1B1 mutations in Chinese patients with primary congenital glaucoma. Mol Vis. 2009;15:432–7. pmid:19247456
    • 82. Azmanov DN, Dimitrova S, Florez L, Cherninkova S, Draganov D, Morar B, et al. LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. Eur J Hum Genet EJHG. 2011 Mar;19(3):326–33. pmid:21081970
    • 83. El-Gayar S, Ganesh A, Chavarria-Soley G, Al-Zuhaibi S, Al-Mjeni R, Raeburn S, et al. Molecular analysis of CYP1B1 in Omani patients with primary congenital glaucoma: a pilot study. Mol Vis. 2009 Jul 8;15:1325–31. pmid:19597567
    • 84. Messina-Baas OM, González-Huerta LM, Chima-Galán C, Kofman-Alfaro SH, Rivera-Vega MR, Babayán-Mena I, et al. Molecular analysis of the CYP1B1 gene: identification of novel truncating mutations in patients with primary congenital glaucoma. Ophthalmic Res. 2007;39(1):17–23. pmid:17164573
    • 85. Alfadhli S, Behbehani A, Elshafey A, Abdelmoaty S, Al-Awadi S. Molecular and clinical evaluation of primary congenital glaucoma in Kuwait. Am J Ophthalmol. 2006 Mar;141(3):512–6. pmid:16490498
    • 86. Martin SN, Sutherland J, Levin AV, Klose R, Priston M, Héon E. Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness. J Med Genet. 2000 Jun;37(6):422–7. pmid:10851252
    • 87. Khan AO, Aldahmesh MA, Al-Abdi L, Mohamed JY, Hashem M, Al-Ghamdi I, et al. Molecular characterization of newborn glaucoma including a distinct aniridic phenotype. Ophthalmic Genet. 2011 Sep;32(3):138–42. pmid:21306220
    • 88. Stoilov IR, Costa VP, Vasconcellos JPC, Melo MB, Betinjane AJ, Carani JCE, et al. Molecular genetics of primary congenital glaucoma in Brazil. Invest Ophthalmol Vis Sci. 2002 Jun;43(6):1820–7. pmid:12036985
    • 89. Bejjani BA, Stockton DW, Lewis RA, Tomey KF, Dueker DK, Jabak M, et al. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet. 2000 Feb 12;9(3):367–74. pmid:10655546
    • 90. Hadrami M, Bonnet C, Zeitz C, Veten F, Biya M, Hamed CT, et al. Mutation profile of glaucoma candidate genes in Mauritanian families with primary congenital glaucoma. Mol Vis. 2019;25:373–81. pmid:31367175
    • 91. Tehreem R, Arooj A, Siddiqui SN, Naz S, Afshan K, Firasat S. Mutation screening of the CYP1B1 gene reveals thirteen novel disease-causing variants in consanguineous Pakistani families causing primary congenital glaucoma. PloS One. 2022;17(9):e0274335. pmid:36083974
    • 92. Kim HJ, Suh W, Park SC, Kim CY, Park KH, Kook MS, et al. Mutation spectrum of CYP1B1 and MYOC genes in Korean patients with primary congenital glaucoma. Mol Vis. 2011;17:2093–101. pmid:21850185
    • 93. Tanwar M, Dada T, Sihota R, Das TK, Yadav U, Dada R. Mutation spectrum of CYP1B1 in North Indian congenital glaucoma patients. Mol Vis. 2009 Jun 13;15:1200–9. pmid:19536304
    • 94. Fuse N, Miyazawa A, Takahashi K, Noro M, Nakazawa T, Nishida K. Mutation spectrum of the CYP1B1 gene for congenital glaucoma in the Japanese population. Jpn J Ophthalmol. 2010 Jan;54(1):1–6. pmid:20151268
    • 95. Reddy ABM, Kaur K, Mandal AK, Panicker SG, Thomas R, Hasnain SE, et al. Mutation spectrum of the CYP1B1 gene in Indian primary congenital glaucoma patients. Mol Vis. 2004 Sep 30;10:696–702. pmid:15475877
    • 96. Emamalizadeh B, Daneshmandpour Y, Kazeminasb S, Aghaei Moghadam E, Bahmanpour Z, Alehabib E, et al. Mutational analysis of CYP1B1 gene in Iranian pedigrees with glaucoma reveals known and novel mutations. Int Ophthalmol. 2021 Oct;41(10):3269–76. pmid:34019190
    • 97. Afzal R, Firasat S, Kaul H, Ahmed B, Siddiqui SN, Zafar SN, et al. Mutational analysis of the CYP1B1 gene in Pakistani primary congenital glaucoma patients: Identification of four known and a novel causative variant at the 3’ splice acceptor site of intron 2. Congenit Anom. 2019 Sep;59(5):152–61. pmid:30270463
    • 98. Bagiyeva S, Marfany G, Gonzalez-Angulo O, Gonzalez-Duarte R. Mutational screening of CYP1B1 in Turkish PCG families and functional analyses of newly detected mutations. Mol Vis. 2007 Aug 27;13:1458–68. pmid:17893647
    • 99. Sheikh SA, Waryah AM, Narsani AK, Shaikh H, Gilal IA, Shah K, et al. Mutational spectrum of the CYP1B1 gene in Pakistani patients with primary congenital glaucoma: novel variants and genotype-phenotype correlations. Mol Vis. 2014;20:991–1001. pmid:25018621
    • 100. Kaushik S, Choudhary S, Kaur A, Srivastava P, Pokharel B, Akella M, et al. Neonatal-Onset Congenital Ectropion Uveae May Be Caused by a Distinct CYP1B1 Pathologic Variant. Am J Ophthalmol. 2022 Jul;239:54–65. pmid:35085548
    • 101. Ohtake Y, Kubota R, Tanino T, Miyata H, Mashima Y. Novel compound heterozygous mutations in the cytochrome P4501B1 gene (CYP1B1) in a Japanese patient with primary congenital glaucoma. Ophthalmic Genet. 2000 Sep;21(3):191–3. pmid:11184479
    • 102. Firasat S, Riazuddin SA, Khan SN, Riazuddin S. Novel CYP1B1 mutations in consanguineous Pakistani families with primary congenital glaucoma. Mol Vis. 2008;14:2002–9. pmid:18989382
    • 103. Colomb E, Kaplan J, Garchon HJ. Novel cytochrome P450 1B1 (CYP1B1) mutations in patients with primary congenital glaucoma in France. Hum Mutat. 2003 Dec;22(6):496. pmid:14635112
    • 104. Mashima Y, Suzuki Y, Sergeev Y, Ohtake Y, Tanino T, Kimura I, et al. Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2211–6. pmid:11527932
    • 105. López-Garrido MP, Medina-Trillo C, Morales-Fernandez L, Garcia-Feijoo J, Martínez-de-la-Casa JM, García-Antón M, et al. Null CYP1B1 genotypes in primary congenital and nondominant juvenile glaucoma. Ophthalmology. 2013 Apr;120(4):716–23. pmid:23218183
    • 106. Yazdani S, Miraftabi A, Pakravan M, Ghahari E, Tousi BK, Sedigh M, et al. Phenotype and Genotype Correlation in Iranian Primary Congenital Glaucoma Patients. J Glaucoma. 2016 Jan;25(1):33–8. pmid:25580891
    • 107. Ohtake Y, Tanino T, Suzuki Y, Miyata H, Taomoto M, Azuma N, et al. Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma. Br J Ophthalmol. 2003 Mar;87(3):302–4. pmid:12598442
    • 108. Dimasi DP, Hewitt AW, Straga T, Pater J, MacKinnon JR, Elder JE, et al. Prevalence of CYP1B1 mutations in Australian patients with primary congenital glaucoma. Clin Genet. 2007 Sep;72(3):255–60. pmid:17718864
    • 109. Chavarria-Soley G, Michels-Rautenstrauss K, Pasutto F, Flikier D, Flikier P, Cirak S, et al. Primary congenital glaucoma and Rieger’s anomaly: extended haplotypes reveal founder effects for eight distinct CYP1B1 mutations. Mol Vis. 2006 May 22;12:523–31. pmid:16735994
    • 110. Tran HT, Tran HT, Luong LH, Nguyen TS, Nguyen HQ, Vu TT, et al. Primary congenital glaucoma in Vietnam: analysis and identification of novel CYP1B1 variants. Ophthalmic Genet. 2019 Jun;40(3):286–7. pmid:31149863
    • 111. Soley GC, Bosse KA, Flikier D, Flikier P, Azofeifa J, Mardin CY, et al. Primary congenital glaucoma: a novel single-nucleotide deletion and varying phenotypic expression for the 1,546–1,555dup mutation in the GLC3A (CYP1B1) gene in 2 families of different ethnic origin. J Glaucoma. 2003 Feb;12(1):27–30. pmid:12567107
    • 112. Michels-Rautenstrauss KG, Mardin CY, Zenker M, Jordan N, Gusek-Schneider GC, Rautenstrauss BW. Primary congenital glaucoma: three case reports on novel mutations and combinations of mutations in the GLC3A (CYP1B1) gene. J Glaucoma. 2001 Aug;10(4):354–7. pmid:11558822
    • 113. Abu-Amero KK, Osman EA, Mousa A, Wheeler J, Whigham B, Allingham RR, et al. Screening of CYP1B1 and LTBP2 genes in Saudi families with primary congenital glaucoma: genotype-phenotype correlation. Mol Vis. 2011;17:2911–9. pmid:22128238
    • 114. Hilal L, Boutayeb S, Serrou A, Refass-Buret L, Shisseh H, Bencherifa F, et al. Screening of CYP1B1 and MYOC in Moroccan families with primary congenital glaucoma: three novel mutations in CYP1B1. Mol Vis. 2010 Jul 2;16:1215–26. pmid:20664688
    • 115. Ivanoshchuk DE, Mikhailova SV, Fenkova OG, Shakhtshneider EV, Fursova AZ, Bychkov IY, et al. Screening of West Siberian patients with primary congenital glaucoma for CYP1B1 gene mutations. Vavilovskii Zhurnal Genet Sel. 2020 Dec;24(8):861–7. pmid:35087999
    • 116. Suri F, Chitsazian F, Khoramian-Tusi B, Amini H, Yazdani S, Nilforooshan N, et al. Sex Bias in Primary Congenital Glaucoma Patients with and without CYP1B1 Mutations. J Ophthalmic Vis Res. 2009 Apr;4(2):75–8. pmid:23198051
    • 117. Cella W, de Vasconcellos JPC, de Melo MB, Kneipp B, Costa FF, Longui CA, et al. Structural assessment of PITX2, FOXC1, CYP1B1, and GJA1 genes in patients with Axenfeld-Rieger syndrome with developmental glaucoma. Invest Ophthalmol Vis Sci. 2006 May;47(5):1803–9. pmid:16638984
    • 118. Milla E, Duch S, Gamundi MJ, Carballo M. Last results of the spanish multicenter genetic glaucoma group. Invest Ophthalmol Vis Sci [Internet]. 2013;54(15). Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L628678471&from=export
    • 119. Daneshvar R, Arab F, Doosti M, Nassiri M, Ghayoor Karimiani E. Three novel CYP1B1 mutations (p.L480P, p.S476P, p.R175P) in Primary Congenital Glaucoma Cases residing in Eastern Iran. Eur J Hum Genet. 2019;26((Daneshvar R.) Mashhad University of Medical Sciences, Mashhad, Iran):845.
    • 120. Waryah YM, Iqbal M, Sheikh SA, Baig MA, Narsani AK, Atif M, et al. Two novel variants in CYP1B1 gene: a major contributor of autosomal recessive primary congenital glaucoma with allelic heterogeneity in Pakistani patients. Int J Ophthalmol. 2019;12(1):8–15. pmid:30662834
    • 121. Suri F, Yazdani S, Narooie-Nejhad M, Zargar SJ, Paylakhi SH, Zeinali S, et al. Variable expressivity and high penetrance of CYP1B1 mutations associated with primary congenital glaucoma. Ophthalmology. 2009 Nov;116(11):2101–9. pmid:19744731
    • 122. Bayat B, Yazdani S, Alavi A, Chiani M, Chitsazian F, Tusi BK, et al. Contributions of MYOC and CYP1B1 mutations to JOAG. Mol Vis. 2008 Mar 13;14:508–17. pmid:18385784
    • 123. Abu-Amero KK, Morales J, Aljasim LA, Edward DP. CYP1B1 Mutations are a Major Contributor to Juvenile-Onset Open Angle Glaucoma in Saudi Arabia. Ophthalmic Genet. 2015 Jun;36(2):184–7. pmid:24099281
    • 124. Souzeau E, Hayes M, Zhou T, Siggs OM, Ridge B, Awadalla MS, et al. Occurrence of CYP1B1 Mutations in Juvenile Open-Angle Glaucoma With Advanced Visual Field Loss. JAMA Ophthalmol. 2015 Jul;133(7):826–33. pmid:25950505
    • 125. Acharya M, Mookherjee S, Bhattacharjee A, Bandyopadhyay AK, Daulat Thakur SK, Bhaduri G, et al. Primary role of CYP1B1 in Indian juvenile-onset POAG patients. Mol Vis. 2006 Apr 20;12:399–404. pmid:16688110
    • 126. Gupta V, Somarajan BI, Walia GK, Kaur J, Kumar S, Gupta S, et al. Role of CYP1B1, p.E229K and p.R368H mutations among 120 families with sporadic juvenile onset open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2018 Feb;256(2):355–62. pmid:29168043
    • 127. Suri F, Kalhor R, Zargar SJ, Nilforooshan N, Yazdani S, Nezari H, et al. Screening of common CYP1B1 mutations in Iranian POAG patients using a microarray-based PrASE protocol. Mol Vis. 2008;14:2349–56. pmid:19096718
    • 128. Lang E, Koller S, Bähr L, Töteberg-Harms M, Atac D, Roulez F, et al. Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals CYP1B1 and FOXC1 Variants as Most Frequent Causes. Transl Vis Sci Technol. 2020 Jun;9(7):47. pmid:32832252
    • 129. Khalil A, Al-Haddad C, Hariri H, Shibbani K, Bitar F, Kurban M, et al. A Novel Mutation in FOXC1 in a Lebanese Family with Congenital Heart Disease and Anterior Segment Dysgenesis: Potential Roles for NFATC1 and DPT in the Phenotypic Variations. Front Cardiovasc Med. 2017;4:58. pmid:28979898
    • 130. Collantes ERA, Delfin MS, Fan B, Torregosa JMR, Siguan-Bell C, Florcruz NVDG, et al. EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma. Hum Mutat. 2022;43(2):240–52. pmid:34923728
    • 131. Pyatla G, Bera S, Anthony A, Mishra A, Moreno-Leon LF, Mandal AK, et al. Multi-Allelic Interactions of Glaucoma and Anterior Segment Dysgenesis-Associated Genes in the Pathogenesis of Primary Congenital Glaucoma. Invest Ophthalmol Vis Sci. 2022;63(7):1131.
    • 132. Li K, Tang M, Xu M, Yu Y. A novel missense mutation of FOXC1 in an Axenfeld-Rieger syndrome patient with a congenital atrial septal defect and sublingual cyst: a case report and literature review. BMC Med Genomics. 2021 Oct 29;14(1):255. pmid:34715865
    • 133. Kumar M, Chambers C, Dhamija R. Axenfeld–Rieger Syndrome and Leukoencephalopathy Caused by a Mutation in FOXC1. Pediatr Neurol. 2017;66((Kumar M.; Chambers C.; Dhamija R., rd3gZ@virginia.edu) Department of Neurology, University of Virginia, Charlottesville, Virginia, United States):113–4. pmid:27697311
    • 134. Khan AO, Aldahmesh MA, Al-Amri A. Heterozygous FOXC1 mutation (M161K) associated with congenital glaucoma and aniridia in an infant and a milder phenotype in her mother. Ophthalmic Genet. 2008 Jun;29(2):67–71. pmid:18484311
    • 135. Ito YA, Footz TK, Berry FB, Mirzayans F, Yu M, Khan AO, et al. Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3573–9. pmid:19279310
    • 136. Pasutto F, Mauri L, Popp B, Sticht H, Ekici A, Piozzi E, et al. Whole exome sequencing reveals a novel de novo FOXC1 mutation in a patient with unrecognized Axenfeld-Rieger syndrome and glaucoma. Gene. 2015 Aug 15;568(1):76–80. pmid:25967385
    • 137. Micheal S, Siddiqui SN, Zafar SN, Villanueva-Mendoza C, Cortés-González V, Khan MI, et al. A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma. PloS One. 2016;11(7):e0160016. pmid:27463523
    • 138. Du RF, Huang H, Fan LL, Li XP, Xia K, Xiang R. A Novel Mutation of FOXC1 (R127L) in an Axenfeld-Rieger Syndrome Family with Glaucoma and Multiple Congenital Heart Diseases. Ophthalmic Genet. 2016;37(1):111–5. pmid:24914578
    • 139. Lehmann OJ, Ebenezer ND, Jordan T, Fox M, Ocaka L, Payne A, et al. Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma. Am J Hum Genet. 2000;67(5):1129–35. pmid:11007653
    • 140. Souzeau E, Siggs OM, Zhou T, Galanopoulos A, Hodson T, Taranath D, et al. Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants. Eur J Hum Genet EJHG. 2017 Jun;25(7):839–47. pmid:28513611
    • 141. Medina-Trillo C, Sánchez-Sánchez F, Aroca-Aguilar JD, Ferre-Fernández JJ, Morales L, Méndez-Hernández CD, et al. Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability. PloS One. 2015;10(3):e0119272. pmid:25786029
    • 142. Fuse N, Takahashi K, Yokokura S, Nishida K. Novel mutations in the FOXC1 gene in Japanese patients with Axenfeld-Rieger syndrome. Mol Vis. 2007 Jun 27;13:1005–9. pmid:17653043
    • 143. Siggs OM, Souzeau E, Pasutto F, Dubowsky A, Smith JEH, Taranath D, et al. Prevalence of FOXC1 Variants in Individuals With a Suspected Diagnosis of Primary Congenital Glaucoma. JAMA Ophthalmol. 2019 Apr 1;137(4):348–55. pmid:30653210
    • 144. Medina-Trillo C, Aroca-Aguilar JD, Ferre-Fernández JJ, Alexandre-Moreno S, Morales L, Méndez-Hernández CD, et al. Role of FOXC2 and PITX2 rare variants associated with mild functional alterations as modifier factors in congenital glaucoma. PloS One. 2019;14(1):e0211029. pmid:30657791
    • 145. Medina-Trillo C, Aroca-Aguilar JD, Méndez-Hernández CD, Morales L, García-Antón M, García-Feijoo J, et al. Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences. Eur J Hum Genet EJHG. 2016 May;24(5):672–80. pmid:26220699
    • 146. Kawase C, Kawase K, Taniguchi T, Sugiyama K, Yamamoto T, Kitazawa Y, et al. Screening for mutations of Axenfeld-Rieger syndrome caused by FOXC1 gene in Japanese patients. J Glaucoma. 2001 Dec;10(6):477–82. pmid:11740218
    • 147. Reis LM, Maheshwari M, Capasso J, Atilla H, Dudakova L, Thompson S, et al. Axenfeld-Rieger syndrome: more than meets the eye. J Med Genet. 2022 Jul 26;jmedgenet-2022-108646. pmid:35882526
    • 148. Prem Senthil M, Knight LSW, Taranath D, Mackey DA, Ruddle JB, Chiang MY, et al. Comparison of Anterior Segment Abnormalities in Individuals With FOXC1 and PITX2 Variants. Cornea. 2022 Aug 1;41(8):1009–15.
    • 149. Kuo DS, Sokol JT, Minogue PJ, Berthoud VM, Slavotinek AM, Beyer EC, et al. Characterization of a variant of gap junction protein α8 identified in a family with hereditary cataract. PloS One. 2017;12(8):e0183438.
    • 150. Micheal S, Siddiqui SN, Zafar SN, Iqbal A, Khan MI, den Hollander AI. Identification of Novel Variants in LTBP2 and PXDN Using Whole-Exome Sequencing in Developmental and Congenital Glaucoma. PloS One. 2016;11(7):e0159259. pmid:27409795
    • 151. Narooie-Nejad M, Paylakhi SH, Shojaee S, Fazlali Z, Rezaei Kanavi M, Nilforushan N, et al. Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Hum Mol Genet. 2009 Oct 15;18(20):3969–77. pmid:19656777
    • 152. Rauf B, Irum B, Khan SY, Kabir F, Naeem MA, Riazuddin S, et al. Novel mutations in LTBP2 identified in familial cases of primary congenital glaucoma. Mol Vis. 2020;26:14–25. pmid:32165823
    • 153. Chen X, Chen Y, Fan BJ, Xia M, Wang L, Sun X. Screening of the LTBP2 gene in 214 Chinese sporadic CYP1B1-negative patients with primary congenital glaucoma. Mol Vis. 2016;22:528–35. pmid:27293371
    • 154. Mohanty K, Tanwar M, Dada R, Dada T. Screening of the LTBP2 gene in a north Indian population with primary congenital glaucoma. Mol Vis. 2013;19:78–84. pmid:23378721
    • 155. Somarajan BI, Gupta S, Mahalingam K, Azmira K, Gupta V. Digenic Inheritance in Juvenile Open-Angle Glaucoma. J Pediatr Genet [Internet]. 2021;((Somarajan B.I.; Gupta S.; Mahalingam K.; Azmira K.; Gupta V., gupta_v20032000@yahoo.com) Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India). Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L634149211&from=export pmid:37090837
    • 156. Zhuo Y hong, Wang M, Wei Y tao, Huang Y lin, Ge J. Analysis of MYOC gene mutation in a Chinese glaucoma family with primary open-angle glaucoma and primary congenital glaucoma. Chin Med J (Engl). 2006 Jul 20;119(14):1210–4. pmid:16863615
    • 157. Ramprasad VL, Sripriya S, Ronnie G, Nancarrow D, Saxena S, Hemamalini A, et al. Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree. Mol Vis. 2005 Nov 3;11:934–40. pmid:16288197
    • 158. Chakrabarti S, Kaur K, Komatireddy S, Acharya M, Devi KR, Mukhopadhyay A, et al. Gln48His is the prevalent myocilin mutation in primary open angle and primary congenital glaucoma phenotypes in India. Mol Vis. 2005 Feb 4;11:111–3. pmid:15723004
    • 159. Kaur K, Reddy ABM, Mukhopadhyay A, Mandal AK, Hasnain SE, Ray K, et al. Myocilin gene implicated in primary congenital glaucoma. Clin Genet. 2005 Apr;67(4):335–40. pmid:15733270
    • 160. Criscione J, Ji W, Jeffries L, McGrath JM, Soloway S, Pusztai L, et al. Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure. Cold Spring Harb Mol Case Stud. 2019 Dec;5(6):a004374. pmid:31653660
    • 161. Shimizu S, Lichter PR, Johnson AT, Zhou Z, Higashi M, Gottfredsdottir M, et al. Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma. Am J Ophthalmol. 2000 Aug;130(2):165–77. pmid:11004290
    • 162. Wirtz MK, Samples JR, Toumanidou V, Charlesworth J, Mikropoulos DG, Kaltsos K, et al. Association of POAG risk factors and the Thr377Met MYOC mutation in an isolated Greek population. Invest Ophthalmol Vis Sci. 2010 Jun;51(6):3055–60. pmid:20107173
    • 163. Damji KF, Song X, Gupta SK, Gao J, Rock W, Bulman DE. Childhood-onset primary open angle glaucoma in a Canadian kindred: clinical and molecular genetic features. Ophthalmic Genet. 1999 Dec;20(4):211–8. pmid:10617918
    • 164. Willoughby CE, Chan LLY, Herd S, Billingsley G, Noordeh N, Levin AV, et al. Defining the pathogenicity of optineurin in juvenile open-angle glaucoma. Invest Ophthalmol Vis Sci. 2004 Sep;45(9):3122–30. pmid:15326130
    • 165. Mimiwati Z, Mackey DA, Craig JE, Mackinnon JR, Rait JL, Liebelt JE, et al. Nail-patella syndrome and its association with glaucoma: a review of eight families. Br J Ophthalmol. 2006 Dec;90(12):1505–9. pmid:16825280
    • 166. Huang X, Li M, Guo X, Li S, Xiao X, Jia X, et al. Mutation analysis of seven known glaucoma-associated genes in Chinese patients with glaucoma. Invest Ophthalmol Vis Sci. 2014 May 13;55(6):3594–602. pmid:24825108
    • 167. Braghini CA, Neshich IAP, Neshich G, Soardi FC, de Mello MP, Costa VP, et al. New mutation in the myocilin gene segregates with juvenile-onset open-angle glaucoma in a Brazilian family. Gene. 2013;523(1):50–7. pmid:23566828
    • 168. Stoilova D, Child A, Brice G, Desai T, Barsoum-Homsy M, Ozdemir N, et al. Novel TIGR/MYOC mutations in families with juvenile onset primary open angle glaucoma. J Med Genet. 1998 Dec;35(12):989–92. pmid:9863594
    • 169. Wei YT, Li YQ, Bai YJ, Wang M, Chen JH, Ge J, et al. Pro370Leu myocilin mutation in a Chinese pedigree with juvenile-onset open angle glaucoma. Mol Vis. 2011;17:1449–56. pmid:21677793
    • 170. Waryah AM, Narsani AK, Sheikh SA, Shaikh H, Shahani MY. The novel heterozygous Thr377Arg MYOC mutation causes severe Juvenile Open Angle Glaucoma in a large Pakistani family. Gene. 2013 Oct 10;528(2):356–9. pmid:23886590
    • 171. Avisar I, Lusky M, Robinson A, Shohat M, Dubois S, Raymond V, et al. The novel Y371D myocilin mutation causes an aggressive form of juvenile open-angle glaucoma in a Caucasian family from the Middle-East. Mol Vis. 2009 Sep 24;15:1945–50. pmid:19784393
    • 172. Stoilova D, Child A, Brice G, Crick RP, Fleck BW, Sarfarazi M. Identification of a new “TIGR” mutation in a family with juvenile-onset primary open angle glaucoma. Ophthalmic Genet. 1997 Sep;18(3):109–18. pmid:9361308
    • 173. Magliyah M, Alsalamah AK, AlOtaibi M, Nowilaty SR. A novel c.980C>G variant in OAT results in identifiable gyrate atrophy phenotype associated with retinal detachment in a young female. Ophthalmic Genet. 2021 Apr;42(2):204–8.
    • 174. Schilter KF, Reis LM, Sorokina EA, Semina EV. Identification of an Alu-repeat-mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype. Mol Genet Genomic Med. 2015 Nov;3(6):490–9. pmid:26740941
    • 175. Chang MS, Han JC, Lee J, Kwun Y, Huh R, Ki CS, et al. A novel splice site mutation in the PAX6 gene in a Korean family with isolated aniridia. Ann Clin Lab Sci. 2015;45(1):90–3. pmid:25696017
    • 176. Gucev Z, Muratovska O, Laban N, Misevska L, Jancevska A, Crolla J, et al. Billateral polycystic kidneys in a girl with WAGR syndrome. Indian J Pediatr. 2011 Oct;78(10):1290–2. pmid:21660403
    • 177. Ouyang J, Cai Z, Guo Y, Nie F, Cao M, Duan X. Detection of a novel PAX6 variant in a Chinese family with multiple ocular abnormalities. BMC Ophthalmol. 2022 Jan 16;22(1):28. pmid:35034608
    • 178. Palayil I, Priya SG, Sivan NVS, Madhivanan N, Venkatachalam PS, Jagadeesan M. Identification of a novel frameshift mutation in PAX6 gene and the clinical management in an Asian Indian aniridia family. Indian J Ophthalmol. 2018 Feb;66(2):229–32. pmid:29380764
    • 179. Kit V, Cunha DL, Hagag AM, Moosajee M. Longitudinal genotype-phenotype analysis in 86 patients with PAX6-related aniridia. JCI Insight. 2021 Jul 22;6(14):e148406. pmid:34101622
    • 180. Wang GM, Prasov L, Richards J, Bohnsack B. Phenotypic variation in a four-generation family with aniridia carrying a novel PAX6 mutation. J AAPOS. 2017;21(4):e36–7.
    • 181. Caglayan AO, Robinson D. Aniridia phenotype and myopia in a turkish boy with a PAX6 gene mutation. Genet Couns Geneva Switz. 2011;22(2):155–9.
    • 182. Gupta V, Somarajan BI, Gupta S, Mahalingam K, Singh A, Sharma A. A new association of PAX6 variation with Juvenile onset open angle glaucoma. J Hum Genet. 2023 Jan 5; pmid:36599958
    • 183. Protas ME, Weh E, Footz T, Kasberger J, Baraban SC, Levin AV, et al. Mutations of conserved non-coding elements of PITX2 in patients with ocular dysgenesis and developmental glaucoma. Hum Mol Genet. 2017 Sep 15;26(18):3630–8. pmid:28911203
    • 184. Kletke SN, Vincent A, Maynes JT, Elbaz U, Mireskandari K, Lam WC, et al. A de novo mutation in PITX2 underlies a unique form of Axenfeld-Rieger syndrome with corneal neovascularization and extensive proliferative vitreoretinopathy. Ophthalmic Genet. 2020;41(4):358–62. pmid:32429730
    • 185. Gupta V, Somarajan BI, Kaur G, Gupta S, Singh R, Pradhan D, et al. Exome sequencing identifies procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 mutations in primary congenital and juvenile glaucoma. Indian J Ophthalmol. 2021 Oct;69(10):2710–6. pmid:34571620
    • 186. Young TL, Whisenhunt KN, Jin J, LaMartina SM, Martin SM, Souma T, et al. SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma. Invest Ophthalmol Vis Sci. 2020 Oct 1;61(12):6. pmid:33027505
    • 187. Qiao Y, Chen Y, Tan C, Sun X, Chen X, Chen J. Screening and Functional Analysis of TEK Mutations in Chinese Children With Primary Congenital Glaucoma. Front Genet. 2021;12:764509. pmid:34956319
    • 188. Fu H, Siggs OM, Knight LSW, Staffieri SE, Ruddle JB, Birsner AE, et al. Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma. J Clin Invest [Internet]. 2022;132(23). Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2021619871&from=export pmid:36453543
    • 189. Passan S, Goyal S, Bhat MA, Singh D, Vanita V. Association of TNF-α gene alterations (c.-238G>A, c.-308G>A, c.-857C>T, c.-863C>A) with primary glaucoma in north Indian cohort. Gene. 2019 Aug 15;709:25–35.
    • 190. Kaur K, Mandal AK, Chakrabarti S. Primary Congenital Glaucoma and the Involvement of CYP1B1. Middle East Afr J Ophthalmol. 2011 Jan;18(1):7–16. pmid:21572728
    • 191. Chen X, Chen Y, Wang L, Jiang D, Wang W, Xia M, et al. CYP1B1 genotype influences the phenotype in primary congenital glaucoma and surgical treatment. Br J Ophthalmol. 2014 Feb;98(2):246–51. pmid:24227805
    • 192. Chakrabarti S, Kaur K, Rao KN, Mandal AK, Kaur I, Parikh RS, et al. The transcription factor gene FOXC1 exhibits a limited role in primary congenital glaucoma. Invest Ophthalmol Vis Sci. 2009 Jan;50(1):75–83. pmid:18708620
    • 193. Berry FB, Lines MA, Oas JM, Footz T, Underhill DA, Gage PJ, et al. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Mol Genet. 2006 Mar 15;15(6):905–19. pmid:16449236
    • 194. Syeda F, Kirchhof P, Fabritz L. PITX2-dependent gene regulation in atrial fibrillation and rhythm control. J Physiol. 2017 Jun 15;595(12):4019–26. pmid:28217939
    • 195. Xu M, Li K, He W. Compound heterozygous mutations in the LTBP2 gene associated with microspherophakia in a Chinese patient: a case report and literature review. BMC Med Genomics. 2021 Sep 17;14(1):227. pmid:34535142
    • 196. Sharma R, Grover A. Myocilin-associated Glaucoma: A Historical Perspective and Recent Research Progress. Mol Vis. 2021;27:480–93. pmid:34497454
    • 197. Park BC, Tibudan M, Samaraweera M, Shen X, Yue BYJT. Interaction between two glaucoma genes, optineurin and myocilin. Genes Cells Devoted Mol Cell Mech. 2007 Aug;12(8):969–79.
    • 198. Murray GI, Melvin WT, Greenlee WF, Burke MD. Regulation, function, and tissue-specific expression of cytochrome P450 CYP1B1. Annu Rev Pharmacol Toxicol. 2001;41:297–316. pmid:11264459
    • 199. Polansky JR, Fauss DJ, Chen P, Chen H, Lütjen-Drecoll E, Johnson D, et al. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmol J Int Ophtalmol Int J Ophthalmol Z Augenheilkd. 1997;211(3):126–39. pmid:9176893
    • 200. Wang HW, Sun P, Chen Y, Jiang LP, Wu HP, Zhang W, et al. Research progress on human genes involved in the pathogenesis of glaucoma (Review). Mol Med Rep. 2018 Jul;18(1):656–74. pmid:29845210
    • 201. Bajaj S, Venkatraman M, Agarwal N, Kothari M. Cross-sectional observational analysis of the genetic referral practices across pediatric ophthalmology outpatient departments in an urban setting. Indian J Ophthalmol. 2022 Jul;70(7):2564–9. pmid:35791157
    • 202. Villalba MF, Grajewski AL, Tekin M, Bademci G, Chang TC. Diagnostic yield of next generation sequencing gene panel assays for early-onset glaucoma in an ethnically diverse population. J AAPOS Off Publ Am Assoc Pediatr Ophthalmol Strabismus. 2022 Dec;26(6):302.e1–302.e6.
    • 203. Jackson D, Malka S, Harding P, Palma J, Dunbar H, Moosajee M. Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom. Am J Med Genet C Semin Med Genet. 2020 Sep;184(3):578–89. pmid:32830442
    • 204. Lenassi E, Clayton-Smith J, Douzgou S, Ramsden SC, Ingram S, Hall G, et al. Clinical utility of genetic testing in 201 preschool children with inherited eye disorders. Genet Med. 2020;22(4):745–51. pmid:31848469
    • 205. Hui EKY, Yam JCS, Rahman F, Pang CP, Kumaramanickavel G. Ophthalmic genetic counselling: emerging trends in practice perspectives in Asia. J Community Genet. 2023 Feb;14(1):81–9. pmid:36322374