The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies

Prog Retin Eye Res. 2021 May:82:100898. doi: 10.1016/j.preteyeres.2020.100898. Epub 2020 Aug 26.


X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic features. Many are X-linked recessive, but several exhibit a phenotype in female carriers, which can help establish diagnosis and yield insights into disease mechanisms. The presence of affected carriers can misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants in the same gene and also highlight limitations of current genetic sequencing methods. X-linked disease frequently arises from loss of function, implying potential for benefit from gene replacement strategies. We review X-inactivation and X-linked inheritance, and explore burden of disease attributable to X-linked genes in our clinically and genetically characterised retinal disease cohort, finding correlation between gene transcript length and numbers of families. We list relevant genes and discuss key clinical features, disease mechanisms, carrier phenotypes and novel experimental therapies. We consider in detail the following: RPGR (associated with retinitis pigmentosa, cone and cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital stationary night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue cone monochromacy, Bornholm eye disease, cone dystrophy), GPR143 (ocular albinism), COL4A5 (Alport syndrome), and NDP (Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR)). We use a recently published transcriptome analysis to explore expression by cell-type and discuss insights from electrophysiology. In the final section, we present an algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy, summarise current experimental therapeutic approaches, and consider questions for future research.

Keywords: Cone-rod dystrophy; Retina; Retinal dystrophies; Retinitis pigmentosa; X-linked genetic diseases; X-linked retinopathies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Calcium Channels, L-Type
  • Eye Proteins / genetics
  • Female
  • Genes, X-Linked
  • Genetic Diseases, X-Linked* / genetics
  • Genetic Diseases, X-Linked* / therapy
  • Humans
  • Male
  • Mutation
  • Night Blindness*
  • Phenotype
  • Retinal Degeneration*


  • CACNA1F protein, human
  • Calcium Channels, L-Type
  • Eye Proteins
  • RPGR protein, human