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Pathogenicity of novel atypical variants leading to choroideremia as determined by functional analyses

Choroideremia is a monogenic X‐linked recessive chorioretinal disease linked to pathogenic variants in the CHM gene. These variants are commonly base‐pair changes, frameshifts, or large deletions. However, a few rare or unusual events comprising large duplications, a retrotransposon insertion, a pseudo‐exon activation, and two c‐98 promoter substitutions have also been described. Following an exhaustive molecular diagnosis, we identified and characterized three novel atypical disease‐causing variants in three unrelated male patients. One is a first‐ever reported Alu insertion within CHM and the other two are nucleotide substitutions, c.‐90C>G and c.‐108A>G, affecting highly conserved promoter positions. RNA analysis combined with western blot and functional assays of patient cells established the pathogenicity of the Alu insertion and the c.‐90C>G alteration. Furthermore, luciferase reporter assays suggested a CHM transcription defect associated with the c.‐90C>G and c.‐108A>G variants. These findings broaden our knowledge of the mutational spectrum and the transcriptional regulation of the CHM gene.