Abstract
BackgroundGenomic mutations in about 200 genes are associated with hereditary retinal diseases. In this study, we screened for the disease-causing gene mutation in a family with X-linked retinal degenerative disease.MethodsPedigree data were collected and genomic DNA was isolated from peripheral blood of family members, who also underwent comprehensive ophthalmic examination including visual acuity, slit-lamp examination, fundus examination and visual field testing at Qilu Hospital of Shandong University. Whole-exome genomic sequencing was used to screen for gene mutations in the male proband. Sanger sequencing was used to confirm the mutation revealed in this family.ResultsTwo affected males underwent ophthalmic examination; retinitis pigmentosa (RP) was diagnosed on the basis of night blindness beginning at an early age, decreasing visual acuity, progressive loss of peripheral vision, attenuation of retinal vessels and pigment disturbance on fundus examination. However, whole-exome sequencing revealed no mutation in RP-associated genes. Instead, we identified a novel hemizygous c.1475_1476insCA mutation in the choroideremia-associated gene (CHM). The mutation was confirmed by Sanger sequencing and further excluded from the possibility as a rare polymorphism. From the genetic data and clinical findings, the diagnosis was corrected to choroideremia (CHM). Further molecular genetic analysis suggested that this novel CHM mutation caused a frame shift (p.Leu492PhefsX7) and encoded a truncated nonfunctional Rab escort protein 1 (REP-1), which caused CHM in this family. Finally, sequencing data for a pregnant female member confirmed that she did not carry the mutation and thus was carrying a healthy infant.ConclusionWe report a novel CHM mutation, c.1475_1476insCA, identified by whole-exome sequencing in a family with X-linked CHM initially diagnosed as RP. Our findings emphasize the value of a diagnostic approach that associates genetic and ophthalmologic data to facilitate the proper clinical diagnosis of rare hereditary retinal diseases such as CHM.
Highlights
Genomic mutations in about 200 genes are associated with hereditary retinal diseases
Sanger sequencing Sanger sequencing confirmed the CHM gene c.1475_ 1476insCA mutation in the affected males IV-2 and IV-5 (Fig. 4). This novel CHM mutation was detected in none of 200 healthy controls, which excluded the mutation as being a rare DNA polymorphism
Sanger sequencing data suggest that affected male III-5 did not have the disease-causing CHM gene mutation, which agreed with his disease-free status
Summary
Genomic mutations in about 200 genes are associated with hereditary retinal diseases. Progressive inherited retinal degenerative diseases, including agerelated macular degeneration and retinitis pigmentosa (RP), as well as the rare choroideremia (CHM), are the leading causes of blindness in developed countries, affecting about one-third of all people older than 75 [2]. RP is the most common retinal hereditary disease and refers to various forms of progressive retinal degeneration with predominantly impaired rod photoreceptors [3]. It is a clinically and genetically highly heterogeneous retinal disease and is characterized by different genetic transmission modes including autosomal dominant, autosomal recessive and X-linked [3, 4].
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