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Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families.

ABSTRACT: Choroideremia (CHM) is an incurable progressive chorioretinal dystrophy. Little is known about the natural disease course of visual acuity in the Japanese population. We aimed to investigate the genetic spectrum of the CHM gene and visual acuity outcomes in 24 CHM patients from 16 Japanese families. We measured decimal best-corrected visual acuity (BCVA) at presentation and follow-up, converted to logMAR units for statistical analysis. Sanger and/or whole-exome sequencing were performed to identify pathogenic CHM variants/deletions. The median age at presentation was 37.0 years (range, 5-76 years). The mean follow-up interval was 8.2 years. BCVA of the better-seeing eye at presentation was significantly worsened with increasing age (r?=?0.515, p??40 years old. A Kaplan-Meier survival curve suggested that a BCVA of Snellen equivalent 20/40 at follow-up remains until the fifties. Fourteen pathogenic variants, 6 of which were novel [c.49?+?5G?>?A, c.116?+?5G?>?A, p.(Gly176Glu, Glu177Ter), p.Tyr531Ter, an exon 2 deletion, and a 5.0-Mb deletion], were identified in 15 families. No variant was found in one family only. Our BCVA outcome data are useful for predicting visual prognosis and determining the timing of intervention in Japanese patients with CHM variants.

SUBMITTER: Hayashi T

PROVIDER: S-EPMC7522719 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families.

Hayashi Takaaki T Kameya Shuhei S Mizobuchi Kei K Kubota Daiki D Kikuchi Sachiko S Yoshitake Kazutoshi K Mizota Atsushi A Murakami Akira A Iwata Takeshi T Nakano Tadashi T

Scientific reports 20200928 1

Choroideremia (CHM) is an incurable progressive chorioretinal dystrophy. Little is known about the natural disease course of visual acuity in the Japanese population. We aimed to investigate the genetic spectrum of the CHM gene and visual acuity outcomes in 24 CHM patients from 16 Japanese families. We measured decimal best-corrected visual acuity (BCVA) at presentation and follow-up, converted to logMAR units for statistical analysis. Sanger and/or whole-exome sequencing were performed to ident ...[more]

PMID: 32985515

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Project description:We report the underlying genotype and explore possible genotypic-phenotypic correlations in a large cohort of choroideremia patients.We studied prospectively a cohort of 79 patients diagnosed within a tertiary referral service for patients with retinal dystrophies. Phenotypic evaluation consisted of clinical examination, including visual acuity and residual retinal area by fundus autofluorescence (FAF). Genotype was established by sequencing. We also investigated whether particular genotypes were associated with more severe phenotypes by performing analysis of covariance (ANCOVA), with visual acuity and FAF as the dependent variables and age as the covariant.A total of 74 (94%) of patients in our cohort had causative mutations by sequencing, the majority of which were anticipated to be null. Of these, 35 (47%) had insertions and deletions, 13 (18%) had mutations predicted to affect splicing, and 26 (35%) had single point mutations. In the latter case, 13 of 21 (62%) pedigrees with single point mutations were C to T transitions at C-phosphate-G (CpG) dinucleotides. These mutations were spread across 5 of only 24 CpG dinucleotides in the entire CHM cDNA. Furthermore, these 5 locations are the only sites at which C to T transitions result in a stop codon. No clear evidence was found for genotype-phenotype correlation except in the instance of a patient with a large deletion involving neighbouring sequences.In patients with a diagnosis of choroideremia made by a specialty service, there is a high likelihood of establishing a genetic diagnosis. The majority of causative mutations appear to be null and, therefore, may benefit from gene replacement therapy. A disproportionate number of single point mutations observed were C to T transitions, consistent with the evolutionary decay of CpG dinucleotides through methylation and subsequent deamination. Hence, the development of choroideremia in such patients may represent the unwanted consequence of human evolution; de novo mutations are predicted to arise at these sites in future generations. (ClinicalTrials.gov number, NCT01461213.).

Dataset Information

Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families.

Publications

Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families.

Similar Datasets

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