A putative frameshift variant in the CHM gene is associated with an unexpected splicing alteration in a choroideremia patient

Abstract Background Due to the limited availability of mRNA analysis data, the number of exonic variants resulting in splicing impairment is underestimated although aberrant splicing correction is a promising therapeutic option to treat monogenic diseases, including choroideremia (CHM), a rare X‐linked eye disorder arising from sequence alteration of the CHM gene. Herein we report an exonic frameshift variant associated with an mRNA splicing alteration that leads to a CHM hypomorphic allele. Methods Total RNA and genomic DNA were extracted from peripheral blood of a patient affected by a mild form of CHM. The CHM gene was analyzed by PCR‐based methods and Sanger sequencing. Results Besides the known c.1335dup frameshift variant, mRNA analysis revealed a splicing alteration that restored the reading frame of the mutant transcript, likely leading to an aberrant protein with residual activity. Bioinformatic analyses identified novel putative exonic splicing enhancer elements and provided clues that also pre‐mRNA secondary structure should be taken into account when exploring splicing mechanisms. Conclusion A careful molecular characterization of the c.1335dup variant's effect explains the relationship between genotype and phenotype severity in a CHM patient and provides new perspectives for the study of therapeutic strategies based on splicing correction in human diseases.