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Rajarshi Mukhopadhyay, Louise Ocaka, Donna S. Mackay, Andrew R. Webster; de Novo Mutation In The Chm Gene In A Family With Choroideraemia. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5387.
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Choroideraemia is an X-linked retinal dystrophy predominantly affecting men with early onset night blindness, progressive visual field loss and eventual loss of central vision. Most mutations in the CHM gene translating REP-1 protein implicated in choroideraemia are null. The carrier females have distinct signs identifiable on clinical examination, helping in their identification and counselling. The purpose of this study is to describe the phenotype and genotype of an affected male with choroideraemia and his unaffected mother.
Full ophthalmic clinical examination, autofluorescence, and spectral-domain optical coherence tomogram of a 28-year old male with night blindness and diminished visual field was performed and choroideraemia diagnosed. Clinical examination and imaging of his asymptomatic 62-year old mother was performed. Sanger sequencing of the CHM gene in mother and son was conducted using standard methods. Four microsatellite markers were used to determine the haplotype of about 2.7 Mb region in Xq surrounding the CHM gene in mother and son using manufacturer’s protocols.
There was no suggestion of other affected males, despite a comprehensive maternal family history. Extensive loss of outer layers of the retina and choroid was seen in the affected male, with sparing of the fovea. The asymptomatic mother was completely normal on examination and imaging. Sequencing showed a novel c.941-2 A>G splice-site mutation in the CHM gene present in the son but absent in the mother. This mutation is predicted to abolish the splice acceptor site of intron 7. Haplotype analysis identified the chromosome inherited by the son from his mother, confirming maternity and suggesting a maternal germline de novo mutation.
This is the first report of a de novo mutation affecting the CHM gene, as far as the authors are aware. The possibility of de novo mutation should be considered in the diagnosis of new cases.
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