Genotype-Phenotype of Isolated Foveal Hypoplasia in a Large Cohort: Minor Iris Changes as an Indicator of PAX6 Involvement

Invest Ophthalmol Vis Sci. 2021 Aug 2;62(10):23. doi: 10.1167/iovs.62.10.23.

Abstract

Purpose: Foveal hypoplasia (FVH) is defined as the lack of fovea with a relatively preserved neuroretina, occurring either as an isolated FVH (IFVH) condition or associated with other diseases. This study aimed to systemically molecularly characterize IFVH.

Methods: Genetic defects in 33 families with IFVH were analyzed by exome sequencing. Variants in three genes (PAX6, SLC38A8, and AHR) were selected and evaluated with multistep bioinformatic tools.

Results: Mutations in the three genes were identified in 69.7% (23/33) of families with IFVH and infantile nystagmus, including 18 families with PAX6 mutations, 5 with SLC38A8 mutations, but none with AHR mutations. Clinical data from 32 patients in the 23 families showed FVH, infantile nystagmus, and full iris. Careful follow-up visits revealed subtle changes in iris in 9 of 14 patients with PAX6 variants. The PAX6 variants of the 18 families (15 missense and one stop-loss) were mostly located in the C-terminal region of the paired box domain. Variants in AHR, SLC38A8, and PAX6 contributed to IFVH in one (2%), 25 (45%), and 30 (53%) families with identified genetic defects (23 families in this study and 33 reported previously), respectively.

Conclusions: PAX6 and SLC38A8 mutations are the main cause of IFVH based on our data and a systematic review. IFVH-associated PAX6 variants are mostly missense with a specific location, indicating a specific correlation of these variants with IFVH but not with typical aniridia. Full iris with subtle structural abnormalities is more common in patients with PAX6-associated IFVH, suggesting a potential diagnostic indicator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / genetics*
  • DNA Mutational Analysis
  • Eye Diseases, Hereditary / genetics*
  • Eye Diseases, Hereditary / metabolism
  • Female
  • Fovea Centralis / abnormalities*
  • Fovea Centralis / metabolism*
  • Genotype
  • Humans
  • Male
  • Mutation, Missense*
  • Nystagmus, Congenital / genetics*
  • Nystagmus, Congenital / metabolism
  • PAX6 Transcription Factor / genetics*
  • PAX6 Transcription Factor / metabolism
  • Pedigree
  • Phenotype

Substances

  • PAX6 Transcription Factor
  • PAX6 protein, human
  • DNA

Supplementary concepts

  • Foveal Hypoplasia, Isolated