Objective To describe a large family with a novel mutation in CHM.
Methods Family members were characterized using clinical examination, wide-field fundus photography, wide-field autofluorescence, and spectral domain optical coherence tomography. The CHM mutation was identified with the National Institutes of Health–sponsored eyeGene program.
Results A novel nonsense CHM mutation (T1194G), resulting in a premature stop (Y398X) and loss of the final one-third C-terminal portion of the protein, was identified. A large pedigree was generated from information provided by the twice-married proband. Seven men (aged 27-39 years) and 7 women (aged 22-89 years) were evaluated. Affected men showed characteristic peripheral chorioretinal atrophy with islands of macular sparing. Female carriers exhibited a wide range of variability, from mild pigmentary alterations to significant chorioretinal atrophy with severe vision loss. Older women tended to have a more severe phenotype. Autofluorescence demonstrating subfoveal loss or absence of retinal pigment epithelium correlated with vision loss in both sexes. Spectral domain optical coherence tomography demonstrated dynamic changes and remodeling of the outer retina over time, including focal thickening, drusenlike deposits, and disruption to photoreceptor inner segment and outer segment junctions in young female carriers.
Conclusions CHM (T1194G) is a novel mutation that manifests a wide range of phenotypic variability in a single family with a trend toward more severe phenotypes in older female carriers. Our findings emphasize the importance of considering X-linked diseases by carefully evaluating pedigrees in women with severe manifestations of disease.
Clinical Relevance These findings demonstrate a novel CHM mutation that emphasizes severe posterior pole carrier phenotypes, age-related changes, and early choroideremia disease.