Abstract
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.
Highlights
Inherited retinal diseases are a frequent cause of blindness in pae diatric and working age populations in many countries (Liew et al, 2014; Rahman et al, 2020; Solebo and Rahi, 2014; Solebo et al, 2017)
Some female carriers may manifest features of X-linked recessive disease leading to apparent pseudo-dominant inheritance (Fig. 1B). This led historically to the conclusion that X-linked inheritance was rare in retinal dystrophies (Francois, 1961), which was subsequently demon strated to be erroneous, with X-linked inheritance being demonstrated in up to a fifth of families with Retinitis pigmentosa (RP) (Bird, 1975; Jay, 1982). Such errors are still being corrected: in a recent publication, we showed that disease in a family previously published as autosomal dominant (Downes et al, 2001) was likely to be due to a pathogenic variant in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene, and the autosomal variant was likely to be benign (Mahroo et al, 2019)
We have reviewed a diverse range of conditions giving rise to ab normalities in retinal structure or function secondary to pathogenic variants in X-linked genes, concentrating on non-syndromic conditions
Summary
Inherited retinal diseases are a frequent cause of blindness in pae diatric and working age populations in many countries (Liew et al, 2014; Rahman et al, 2020; Solebo and Rahi, 2014; Solebo et al, 2017). Columns of labelled or unlabelled cells are evident in the developing retina indicating inactivation of either X chromosome, as well as radial migration of columns of labelled retinal neuroblasts The latter might explain the pattern of pigmentation seen in carriers of some X-linked retinal diseases such as ocular albinism or choroideremia. More recent testing was less biased, making use of large gene panels as well as whole exome, and whole genome sequencing (as part of national collaborative projects (Carss et al, 2017; Turnbull et al, 2018)) This analysis does not necessarily indicate the proportion of all suspected genetic disease that is X-linked.
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