Synonymous Variant in the CHM Gene Causes Aberrant Splicing in Choroideremia

Abstract

PURPOSE. Choroideremia is an inherited retinal degeneration caused by 280 different pathogenic variants in the CHM gene. Only one silent/synonymous variant (c.1359C>T; p.(Ser453=)) has been reported and was classified as inconclusive based on in silico analysis. This study elucidates the pathogenicity of this variant also found in a Brazilian patient. METHODS. Ophthalmological examinations such as color fundus photography, spectraldomain optical coherence tomography, fundus autofluorescence, and macular integrity assessment microperimetry were performed. The subjects' total RNA was extracted from peripheral blood cells. cDNA was synthesized and the amplification between exon 10 and 14 of the CHM mRNA was performed. The amplification products were sequenced by Sanger sequencing and the results were aligned to the reference sequence. RESULTS. The synonymous variant c.1359C>T p.(Ser453=) in the CHM gene is associated with an error in mRNA processing, leading preferentially to production of an aberrant transcript without exon 11 (p.(Gln451Phefs*3)). This anomalous mRNA production is related to typical choroideremia phenotype. CONCLUSIONS. These molecular findings reinforce the need for more detailed investigation of silent variants in patients with well-defined phenotype of retinal dystrophies. Molecular and clinical findings provided evidence that c.1359C>T (p.(Gln451Phefs*3)) in CHM should be considered a disease-causing variant.

Whole exome sequencing of a family revealed a novel variant in the CHM gene, c.22delG p.(Glu8Serfs*4), which co-segregated with choroideremia

“…Traditionally, choroideremia is typically diagnosed on the basis of family history and the results of clinical examination. Most patients with choroideremia have a characteristic fundus phenotype, which includes RPE atrophy, choriocapillaris loss, retina depigmentation, and choroidal vessels in exposed choroid areas [35]; this phenotype differs from the phenotype observed in patients with retinitis pigmentosa, which includes bone spicule pigmentation, retinal vascular stenosis, and a waxy-pale optic disc [36]. Both patients with retinitis pigmentosa and patients with choroideremia often complain of nyctalopia, visual field restriction, and reduced visual acuity, including blindness in the late stages of disease [37,38]; in addition, some female carriers show mild phenotypes due to a mosaic X-linked inheritance pattern.…”