Somatic mosaicism and skewed X-chromosome inactivation associated with male-pattern choroideremia phenotype in a female patient.

Abstract

Purpose: To report a Japanese female patient with a male-pattern choroideremia phenotype associated with somatic mosaicism and skewed X-chromosome inactivation (XCI).

Methods: A 24-year-old woman underwent comprehensive ophthalmic examinations, including fundus imaging and full-field electroretinography (ERG). Whole-exome sequencing (WES) was performed on leukocyte-derived DNA, with validation by Sanger sequencing of both leukocyte- and buccal mucosa-derived DNA. XCI status was assessed using the HUMARA assay on buccal mucosa-derived DNA.

Results: Despite preserved visual acuity, fundus examination revealed diffuse chorioretinal atrophy with a residual stellate macular island of preserved autofluorescence. Full-field ERG demonstrated non-recordable responses under both dark- and light-adapted conditions. WES identified a pathogenic CHM frameshift variant (c.525_526del) at a low variant allele fraction (VAF: 10%) in leukocyte-derived DNA. The variant was undetectable by Sanger sequencing of leukocyte-derived DNA but was confirmed as a heterozygous allele in buccal mucosa-derived DNA. The 10% VAF was substantially lower than the approximately 50% expected for a constitutional heterozygous variant and was therefore consistent with somatic mosaicism. XCI analysis demonstrated skewing, with a methylated allelic ratio of 83.1:16.9; however, the preferentially inactivated X chromosome could not be phased with the CHM variant.

Conclusions: The molecular findings in this case support somatic mosaicism. Skewed XCI was also observed in buccal mucosa, but its contribution to the phenotype remains uncertain because the preferentially inactivated X chromosome could not be phased with the CHM variant and the HUMARA assay did not resolve XCI within variant-bearing cells. Choroideremia should be considered in the differential diagnosis of female patients with severe chorioretinal atrophy, even in the absence of a family history.