The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype.
OBJECTIVE
We report the underlying genotype and explore possible genotypic-phenotypic correlations in a large cohort of choroideremia patients.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.).
Nuffield Laboratory of Ophthalmology, University of Oxford West Wing, John Radcliffe Hospital, Oxford, United Kingdom 2Oxford Eye Hospital, University of Oxford NHS Trust, West Wing, John Radcliffe Hospital, Oxford, United Kingdom 3Save Sight Institute, Sydney University, Sydney, New South Wales, Australia 4Sydney Eye Hospital, Sydney, New South Wales, Australia.
Matthew P
MP
Simunovic
Nuffield Laboratory of Ophthalmology, University of Oxford West Wing, John Radcliffe Hospital, Oxford, United Kingdom 2Oxford Eye Hospital, University of Oxford NHS Trust, West Wing, John Radcliffe Hospital, Oxford, United Kingdom.
Jasleen K
JK
Jolly
Nuffield Laboratory of Ophthalmology, University of Oxford West Wing, John Radcliffe Hospital, Oxford, United Kingdom 2Oxford Eye Hospital, University of Oxford NHS Trust, West Wing, John Radcliffe Hospital, Oxford, United Kingdom.
Kanmin
K
Xue
Nuffield Laboratory of Ophthalmology, University of Oxford West Wing, John Radcliffe Hospital, Oxford, United Kingdom 2Oxford Eye Hospital, University of Oxford NHS Trust, West Wing, John Radcliffe Hospital, Oxford, United Kingdom.
Thomas L
TL
Edwards
Nuffield Laboratory of Ophthalmology, University of Oxford West Wing, John Radcliffe Hospital, Oxford, United Kingdom 2Oxford Eye Hospital, University of Oxford NHS Trust, West Wing, John Radcliffe Hospital, Oxford, United Kingdom.
Markus
M
Groppe
Nuffield Laboratory of Ophthalmology, University of Oxford West Wing, John Radcliffe Hospital, Oxford, United Kingdom 2Oxford Eye Hospital, University of Oxford NHS Trust, West Wing, John Radcliffe Hospital, Oxford, United Kingdom.
Susan M
SM
Downes
Nuffield Laboratory of Ophthalmology, University of Oxford West Wing, John Radcliffe Hospital, Oxford, United Kingdom 2Oxford Eye Hospital, University of Oxford NHS Trust, West Wing, John Radcliffe Hospital, Oxford, United Kingdom 5Moorfields Eye Hospital, London, United Kingdom.
Robert E
RE
MacLaren
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D015794:Choroideremia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012160:Retina / Q000000981:diagnostic imaging* / Q000378:metabolism; D013997:Time Factors; D014792:Visual Acuity; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D004247:DNA