New CHM Gene Mutation Associated to Severe Phenotype in Carriers of Choroideremia

Abstract

Purpose:: To describe clinical phenotypes and molecular findings in a three generation family with X-linked choroideremia, consisting of four affected male patients, one fully manifesting carrier female and four asymptomatic or poorly symptomatic carriers.

Methods:: Molecular genetic analysis was conducted using genomic DNA. All the patients underwent a complete ophthalmologic evaluation including, Ishihara color test, best-corrected visual acuity by Snellen charts, slitlamp biomicroscopy, dilated fundus oculi examination, fundus photography and elettroretinography (ERG).Fundus autofluorescence, fluorescein angiography (FAG), indocyanine green fluorescence angiography (ICG), fundus related perimetry (MP1) and optical coherence tomography (OCT) were also performed, in order to get a more detailed definition of the clinical features.

Results:: Family's pedigree indicated that all symptomatic females are obligate carriera. Mutational analysis of the CHM gene revealed a previously undescribed gene alteration involving exon 12.The clinical findings in the manifesting carrier were typical for advanced choroideremia, with an early age of onset and a rapid progressive evolution. A much less severe retinal pathology was observed in the affected males, among which the worst phenotype was observed in the younger subject of the second generation. Carriers and affected of the third generation presented an earlier onset of the symptoms and of the electrophysiological alterations, compared to the older subjects.

Conclusions:: The clinical investigation revealed an high intra-familiar variability in age of onset and in disease progression. The most severe findings were observed in the manifesting carrier. In addition to the previously reported findings, we observed characteristic alteration in ICG, MP1 and OCT, providing additional criteria for diagnosis. The large variation of the clinical phenotype among patients carrying the same CHM gene defect suggests that the severity of choroideremia could be largely related to additional factors independent from the CHM gene mutation, which may include modifier genes.

Keywords: gene screening • choroid • inner retina dysfunction: hereditary