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Julia Zhu, Kirk Stephenson, Adrian Dockery, Niamh C Wynne, G. Jane Farrar, Paul F Kenna, Giuliana Silvestri, David J Keegan; Severe Female Carrier Phenotype in an Irish Pedigree with Novel Massive Deletion in the CHM Gene. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5426. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Choroideraemia is a X-Linked recessive chorioretinal degenerative condition with progressive atrophy of the choriocapillaris, retinal pigment epithelium and photoreceptors. Affected males show severe early-onset progressive disease, while female carriers typically show mild signs, no symptoms nor progression. Here we describe a family with a novel deletion in the CHM gene in which female carriers manifest extensive progressive chorioretinal degeneration.
As part of the Irish national inherited retinal disease registry (Target 5000), patients with inherited retinal degenerative conditions are recruited. Families, including unaffected relatives, were assessed. Detailed phenotyping included slit lamp biomicroscopy, multimodal imaging and electrodiagnostics. All patients were genotyped via a panel-based next-generation sequencing approach targeting 258 genes.
Two obligate carrier daughters were phenotyped and genotyped via the above study. Both affected males showed extensive chorioretinal atrophy pathognomonic of choroideraemia. The phenotype for carrier daughters varied: daughter 1 showed radial pigmentation at the RPE level and scattered choroidal atrophy, whereas daughter 2 showed more marked reactive pigmentation and extensive symmetrical atrophy of the choroid and outer retina. The manifestations of this female carrier’s phenotype were apparent both anatomically (i.e. optical coherence tomography and en-face imaging) and functionally (i.e. night blindness and visual field constriction). All subjects were found to have massive deletion of the entire CHM gene (Xq21.2) extending 20kb up and downstream (hemizygous in affected males and heterozygous in carrier females).
Typically, female carriers of CHM gene show mild stationary signs with no symptoms, while males are severely affected from a young age. In this case, all females were more severely affected than expected with advanced signs of chorioretinal degeneration and progressive visual decline (subjectively and objectively). This is likely due to a combination of skewed X-inactivation (lyonization) and the severity of CHM gene deletion. This is relevant in the management in this pedigree as females should not be labelled simply as carriers, but as having a mild phenotype of choroideraemia. Active management may be pursued for affected males and females of this pedigree (i.e. current gene therapy trials in CHM).
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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