Comprehensive genetic landscapes and clinical heterogeneity in nanophthalmos: new insights from a large Chinese cohort.

Abstract

Background: Nanophthalmos is a rare ocular condition characterised by a significantly short axial length (AL) and high hyperopia, often associated with various complications. This study aims to provide a comprehensive analysis of the clinical and genetic features of nanophthalmos in a large Chinese cohort.

Methods: A total of 105 patients from unrelated families diagnosed with nanophthalmos were included. Genetic testing was performed using whole exome sequencing to identify variants in genes associated with the condition. Clinical features, including demographic data, the presence of accompanying clinical findings and various ocular parameters, were compared across different genetic groups.

Results: Whole exome sequencing revealed variants in four key genes: PRSS56, MFRP, MYRF and TMEM98, with a detection rate of 71.43%. Autosomal recessive genes (PRSS56 and MFRP) were associated with shorter AL, higher hyperopia, shallower vitreous chamber depth and steeper corneal curvatures (larger K1 and K2). In contrast, autosomal dominant genes (MYRF and TMEM98) were linked to earlier onset of glaucoma and a higher incidence of multiple ciliary body cysts. In the patients carrying variants in PRSS56 and MFRP, biallelic variants were associated with more severe phenotypes, including more extreme ocular parameters and increased risks of specific complications, compared with monoallelic variants.

Conclusion: This study represents the largest cohort of nanophthalmos patients reported to date, expanding the genetic and clinical understanding of the condition. It identifies novel variants and provides valuable insights into genotype-phenotype correlations, highlighting the impact of genetic variation on the disease severity and associated complications of nanophthalmos.