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.

Figure 1

Pedigrees of the families. Round symbols indicate females; square symbols, males; black symbols, Axenfeld-Rieger Syndrome; grey symbols; primary open-angle glaucoma, dashed symbols; primary congenital glaucoma, unfilled symbols, unaffected; diagonal line, deceased; arrow, proband; D, sperm donor; +/−, presence/absence of the gene variant. (a) Families with FOXC1 variants. (b) Families with PITX2 variants.

Figure 2

Distribution of the identified variants in the FOXC1 (a) and PITX2 proteins (b). Missense variants are underlined.

Figure 3

Clinical photographs of individuals with ocular features of Axenfeld-Rieger Malformation. Photographs in (a–c) showing the right eye (left panel) and the left eye (right panel). (a) Slit lamp photos showing corectopia in the left panel, iris stromal hypoplasia in both eyes and posterior embryotoxon (black arrows) in both eyes (individual 9B). (b) Slit lamp photos showing corectopia, pseudopolycoria (black arrows) and iris stromal hypoplasia in both eyes (individual 18B). (c) Slit lamp photos showing corectopia and posterior embryotoxon (black arrows) in both eyes (individual 12). (d) Gonioscopy showing irido-corneal adhesions (black arrow, left panel) and photo showing the presence of breaks in the Descemet’s membrane (Haab’s striae, white arrow, right panel; individual 5A).

Figure 4

Clinical photographs of individuals with glaucoma and no or mild ocular features of Axenfeld-Rieger malformation after re-examination. Photographs in a showing the right eye (left panel) and the left eye (right panel). (a) Slit lamp photos showing iris stromal hypoplasia and diffuse posterior embryotoxon in both eyes (individual 15D). (b) Slit lamp photo showing the absence of iris anomalies and diffuse posterior embryotoxon in the left panel and gonioscopy showing mild irido-corneal adhesions (white arrow) in the right panel (individual 11A). (c) Slit lamp photo showing posterior embryotoxon (black arrow) in the left panel and gonioscopy showing mild irido-corneal adhesions (black arrow) in the right panel (individual 6B).