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Paul Kenna, Matthew Carrigan, Conor Patrick Malone, Emma Duignan, G Jane Farrar; CHM and RPE65: A diagnostic paradox resolved by Next Generation Sequencing. Invest. Ophthalmol. Vis. Sci. 2016;57(12):663.
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© ARVO (1962-2015); The Authors (2016-present)
To present a cryptic case of autosomal recessive RPE65-mediated retinitis pigmentosa, identified by next generation sequencing (NGS), in a clinically and genetically confirmed X-linked choroideremia pedigree.
Family members underwent assessment of best-corrected ETDRS visual acuity and Lanthony D-15 colour vision, Goldmann perimetry, slit-lamp biomicroscopy, ISCEV standard electroretinography, colour and autofluorescence fundus photography and spectral-domain optical coherence tomography at the Research Foundation, The Royal Victoria Eye and Ear Hospital, Dublin. Following informed consent, the proband's DNA was sequenced at the Ocular Genetics Unit, Trinity College Dublin, using a targeted-panel approach. Nimblegen SeqCap reagents were used for library preparation and capture, with sequencing taking place on an Illumina MiSeq. Sanger sequencing was used to check the presence and segregation of possible pathogenic sequence variants, identified by NGS, in the family.
Disease transmission was consistent with X-linked inheritance. Next generation sequencing of the proband, clinically diagnosed with X-linked choroideremia, revealed a premature stop mutation in CHM: R239*. Sanger sequencing of his similarly diagnosed maternal first cousin and their respective mothers confirmed, as clinically expected, the presence of the CHM mutation. Sanger sequencing of a third severely affected male, a grand-uncle through the female line of the proband, with advanced retinal degeneration assumed to be due to choroideremia, revealed that the mutation was absent. DNA was re-isolated from a fresh blood sample in case of mislabelling of the original sample and the mutation was confirmed to be definitely absent. Next generation sequencing performed on this member of the pedigree revealed no other CHM mutations to explain the patient's phenotype. Analysis of the sequence data outside of CHM revealed a homozygous mutation in RPE65: R91W, known to cause recessive retinitis pigmentosa with choroidal involvement.
This case demonstrates that, on very rare occasions, the reasonable assumption in clinical genetics that patients with similar clinical presentations in the same pedigree will have the same causative gene mutation might not always be the case. We highlight this case to demonstrate the ability of NGS to reveal unexpected and clinically actionable findings, with relevance particularly to genetic counselling.
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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