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Christina Zeitz, Barbara Kloeckener-Gruissem, Marie-Elise Lancelot, Aurore Germain, Aline Antonio, Fiona Boyard, Mohaind-Said Saddek, Jose Sahel, Isabelle S Audo; A comprehensive molecular analysis of patients with the diagnosis of choroideremia. Invest. Ophthalmol. Vis. Sci. 2016;57(12):661.
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© ARVO (1962-2015); The Authors (2016-present)
Choroideremia is a progressive chorioretinal degeneration with X-linked mode of inheritance. Affected males typically complain of night blindness in early childhood, followed by progressive loss of peripheral vision in association with typical fundus chorioretinal atrophy. The phenotype in female carriers is highly variable with possible patchy areas of chorioretinal atrophy. Most of the mutations in CHM are predicted to lead to complete absence or to a truncated non-functional form of the encoded Rab escort protein 1 (REP1). Due to the successful demonstration of proof of principle for gene replacement therapy for choroideremia, we report genotype-phenotype correlations of a large French cohort of patients with this disease.
Patients of a French cohort underwent a full ophthalmic examination. Informed consent was obtained from each patient and available unaffected family members. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee. The DNA of 23 index patients with a clinical diagnosis of choroideremia and available family members was extracted and screened for CHM mutations by Sanger sequencing. In cases for which CHM could not be amplified, surrounding genes were screened to estimate the size of deletions. Co-segregation was performed in available family members.
All 23 index patients revealed a CHM mutation, of which 16 were novel. The mutation spectrum comprises 2 complete gene deletions, with an estimated maximal size of 3.36 and 6.05 Mb, 1 single and 2 multiple exon deletions, 8 small deletions, duplications and deletion-insertions, 3 nonsense mutations, 4 splice site mutations and 2 missense mutations predicted to be pathogenic. All mutations co-segregated with the phenotype with some carriers affected. All mutations were unique except the novel nonsense mutation, p.Gln96*, which occurred in two unrelated patients. Phenotypic correlations revealed a relatively homogeneous course of the disease with central foveal preservation until the mid 50s.
In our study we found the large majority of mutations to lead to truncated CHM gene and likely absence of a functional protein. This is in agreement with the previous findings where to date of the ~200 different CHM mutations the majority also represents truncating mutations. Our precise genotype-phenotype data are a prerequisite for future gene therapy trials.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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