Genetic Analysis of Developmental Ocular Disorders

Abstract

Purpose : Developmental ocular disorders encompass a broad range of ocular conditions which are typically present at birth, including anophthalmia/microphthalmia, coloboma, Axenfeld-Rieger anomaly, Peters anomaly, aniridia, congenital glaucoma, and congenital cataract. A large number of genes have been implicated in these conditions but the proportion of developmental ocular disorders which can be explained by mutations in known genes is not clear.

Methods : In order to genetically characterize a cohort of 366 probands with developmental ocular conditions, we performed a combination of single gene sequencing, quantitative PCR, array comparative genomic hybridization, and whole exome sequencing.

Results : Pathogenic variants were identified in 175 probands (48%); the majority of pathogenic variants were intragenic (136; 78%) but causative deletions/duplications were identified in 39 (22%) including 6 which affected only the regulatory region of the gene. The rate of pathogenic variant detection varied by diagnosis. Probands referred with a diagnosis of aniridia or Axenfeld-Rieger anomaly had the highest rate of causative variant identification (72% and 84%, respectively). Interestingly, these groups also showed the highest rate of copy number variations with coding region deletions accounting for 22% and 34% of pathogenic variants and regulatory region deletions accounting for 11% and 4% of pathogenic variants, respectively. The rate of causative variant identification was near 40% for probands with anophthalmia/microphthalmia, Peters, congenital cataract, or congenital glaucoma. For patients with ocular conditions which did not fit into one of these categories (eg, ‘atypical aniridia’ or ‘other anterior segment dysgenesis’), the rate of causative variant identification was much lower (2/15 (13%) and 3/34 (8%), respectively).

Conclusions : These results suggest that while some diagnoses are largely explained by disruption of one or two known genes, most developmental ocular conditions are highly heterogeneous with the majority of causes yet to be determined. These results also highlight the importance of regulatory region deletions in some conditions and suggest that screening for these types of copy number variations affecting other ocular genes is likely to identify additional pathogenic variants.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.