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.

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

“…For ASD without glaucoma, there is a growing body of evidence suggesting that the glaucoma risk differs among different genetic causes. 39 For aniridia, genetic testing is particularly important as it allows early detection/exclusion of two molecular subtypes (accounting for~10% of aniridia cases) that are associated with life limiting complications: WAGR syndrome [MIM 194072] and ACTA2-related multisystemic smooth muscle dysfunction [MIM 613834]. 40 For albinism, it is known that syndromic forms of the disease (HPS and Chediak-Higashi syndrome [MIM 214500]) can be overlooked, especially in young children.…”

A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure

“…Indeed, deleterious mutations in FOXC1 and PITX2 can cause Axenfeld-Rieger syndrome, an anterior segment dysgenesis disorder characterized by anomalies in the anterior chamber angle, including defects in the drainage structures of the eye 30 – 32 . A major consequence of angle dysgenesis is an increase in IOP leading to the development of early-onset glaucoma, with FOXC1 mutation carriers having a younger age at diagnosis in comparison with PITX2 mutation carriers (6 vs. 18 years, respectively) 33 . Therefore, it is likely that common variants in FOXC1 and PITX2 mildly impact the drainage structures, and, in combination with defects of other genetic variants contribute to elevated IOP.…”

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

“…Anterior segment dysgenesis englobes a wild spectrum of ocular defects that include among others the ARS, which is frequently linked to severe functional alterations of either FOXC1 and/or PITX2 ( 28 – 30 ). The mutations associated with the ARS phenotype can range from frameshift mutations resulting in premature termination of translation in the forkhead domain or homeodomain, missense mutations reducing transactivation and protein interactions, and nonsense mutations causing haploinsufficiency of the gene product.…”