Genetics of anterior segment dysgenesis disorders

Abstract

Purpose of review: Anterior segment dysgenesis (ASD) disorders encompass a spectrum of developmental conditions affecting the cornea, iris, and lens and are generally associated with an approximate 50% risk for glaucoma. These conditions are characterized by both autosomal dominant and recessive patterns of inheritance often with incomplete penetrance/variable expressivity. This article summarizes what is known about the genetics of ASD disorders and reviews recent developments.

Recent findings: Mutations in Collagen type IV alpha-1 (COL4A1) and Beta-1,3-galactosyltransferase-like (B3GALTL) have been reported in ASD patients. Novel findings in other well known ocular genes are also presented, among which regulatory region deletions in PAX6 and PITX2 are most notable.

Summary: Although a number of genetic causes have been identified, many ASD conditions are still awaiting genetic elucidation. The majority of characterized ASD genes encode transcription factors; several other genes represent extracellular matrix-related proteins. All of the involved genes play active roles in ocular development and demonstrate conserved functions across species. The use of novel technologies, such as whole genome sequencing/comparative genomic hybridization, is likely to broaden the mutation spectrums in known genes and assist in the identification of novel causative genes as well as modifiers explaining the phenotypic variability of ASD conditions.

Fig 1. Photographs of Patient with PITX2 regulatory region deletion and Axenfeld-Rieger syndrome

*Previously Published* Legend: A. Facial photograph showing maxillary hypoplasia, thin upper lip, and broad nasal bridge. B. Left eye corectopia. C. Right eye posterior embryotoxon. D. Dental anomalies, including maxillary hypodontia. E. Redundant periumbilical skin. Source: Figure 5 from Volkmann BA, Zinkevich NS, Mustonen A, et al. Potential novel mechanism for Axenfeld-Rieger syndrome: deletion of a distant region containing regulatory elements of PITX2. Invest Ophthalmol Vis Sci 2011, 52(3):1450-1459.

Fig. 2. Photograph of an eye affected with Peters anomaly (courtesy of Dr. Alex Levin)

Fig 3. Photographs of Patient with BMP4 deletion and SHORT syndrome

*Previously Published* Legend: A. Patient displays short stature, macrocephaly, decreased subcutaneous fat in upper trunk and head, prominent forehead, sunken eyes, small chin, and hypoplastic nares. B,C. Ocular anomalies include Axenfeld-Rieger anomaly, congenital glaucoma, and microcornea. Source: Figure 1A-C from Reis LM, Tyler RC, Schilter KF, et al. BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome. Hum Genet 2011. Epub ahead of print.