Dataset Information

Novel CHM mutations identified in Chinese families with Choroideremia.

ABSTRACT: Choroideremia is a bilateral and progressive X-linked inherited disease characterized by widespread chorioretinal atrophy with relative sparing of the macular region. It is caused by mutations in the ubiquitously expressed CHM gene, which lead to the absence of the Rab escort protein 1 (REP-1), resulting in prenylation deficiency. Typical fundus appearances for choroideremia were found in 3 probands from three unrelated Chinese families in our study. We firstly used the targeted exome sequencing (TES) technology to detect mutations in CHM gene. Based on an established filtering strategy of data analyses, along with confirmation by co-segregation, a previously reported mutation (c.1584_1587del TGTT, p.V529Hfs*7) was identified in one family, while two novel mutations (c.227_232delinsTGTCATTTCA, p.Q76Lfs*7; c.710dupA, p.Y237_S238delinsX) were identified in the other two families. These findings not only expands the currently limited spectrum of Chinese disease-causing variants in CHM gene, but also increases our understanding of the phenotypic and genotypic correlations of choroideremia, and may potentially lead to improved genetic counseling and specific treatment for families with choroideremia as well.

SUBMITTER: Cai XB

PROVIDER: S-EPMC5064415 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Novel CHM mutations identified in Chinese families with Choroideremia.

Cai Xue-Bi XB Huang Xiu-Feng XF Tong Yi Y Lu Qin-Kang QK Jin Zi-Bing ZB

Scientific reports 20161014

Choroideremia is a bilateral and progressive X-linked inherited disease characterized by widespread chorioretinal atrophy with relative sparing of the macular region. It is caused by mutations in the ubiquitously expressed CHM gene, which lead to the absence of the Rab escort protein 1 (REP-1), resulting in prenylation deficiency. Typical fundus appearances for choroideremia were found in 3 probands from three unrelated Chinese families in our study. We firstly used the targeted exome sequencing ...[more]

PMID: 27739455

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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

Novel CHM mutations identified in Chinese families with Choroideremia.

Publications

Novel CHM mutations identified in Chinese families with Choroideremia.

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