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

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

SUBMITTER: Souzeau E

PROVIDER: S-EPMC5520071 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Souzeau Emmanuelle E Siggs Owen M OM Zhou Tiger T Galanopoulos Anna A Hodson Trevor T Taranath Deepa D Mills Richard A RA Landers John J Pater John J Smith James E JE Elder James E JE Rait Julian L JL Giles Paul P Phakey Vivek V Staffieri Sandra E SE Kearns Lisa S LS Dubowsky Andrew A Mackey David A DA Hewitt Alex W AW Ruddle Jonathan B JB Burdon Kathryn P KP Craig Jamie E JE

European journal of human genetics : EJHG 20170517 7

Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited ...[more]

PMID: 28513611

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Project description:ImportanceBoth primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma.ObjectiveTo investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma.Design, setting, and participantsAustralian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017.Main outcome and measuresIdentification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them.ResultsA total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome.Conclusions and relevanceThese data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.

Project description:ImportanceThree leading disease causes of age-related visual loss are cataract, age-related macular degeneration (AMD), and glaucoma. Although all 3 eye diseases have been implicated with falls and fracture risk, evidence is mixed, with the contribution of different eye diseases being uncertain.ObjectiveTo examine whether people with cataract, AMD, or glaucoma have higher risks of falls or fractures than those without.Design, setting, and participantsThis cohort study was a population-based study in England using routinely collected electronic health records from the Clinical Practice Research Datalink (CPRD) GOLD and Aurum primary care databases with linked hospitalization and mortality records from 2007 to 2020. Participants were people with cataract, AMD, or glaucoma matched to comparators (1:5) by age, sex, and general practice. Data were analyzed from May 2021 to June 2023.ExposuresFor each eye disease, we estimated the risk of falls or fractures using separate multivariable Cox proportional hazards regression models.Main outcomesTwo primary outcomes were incident falls and incident fractures derived from general practice, hospital, and mortality records. Secondary outcomes were incident fractures of specific body sites.ResultsA total of 410 476 people with cataract, 75 622 with AMD, and 90 177 with glaucoma were matched (1:5) to 2 034 194 (no cataract), 375 548 (no AMD), and 448 179 (no glaucoma) comparators. The mean (SD) age was 73.8 (11.0) years, 79.4 (9.4) years, and 69.8 (13.1) years for participants with cataract, AMD, or glaucoma, respectively. Compared with comparators, there was an increased risk of falls in those with cataract (adjusted hazard ratio [HR], 1.36; 95% CI, 1.35-1.38), AMD (HR, 1.25; 95% CI, 1.23-1.27), and glaucoma (HR, 1.38; 95% CI, 1.35-1.41). Likewise for fractures, there were increased risks in all eye diseases, with an HR of 1.28 (95% CI, 1.27-1.30) in the cataract cohort, an HR of 1.18 (95% CI, 1.15-1.21) for AMD, and an HR of 1.31 (95% CI, 1.27-1.35) for glaucoma. Site-specific fracture analyses revealed increases in almost all body sites (including hip, spine, forearm, skull or facial bones, pelvis, ribs or sternum, and lower leg fractures) compared with matched comparators.Conclusions and relevanceThe results of this study support recognition that people with 1 or more of these eye diseases are at increased risk of both falls and fractures. They may benefit from improved advice, access, and referrals to falls prevention services.

Dataset Information

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

Publications

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

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