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Emma Sara Duignan, Matt Carrigan, Jane Farrar, Paul Kenna; Further evidence suggesting pathogenicity of the PROM1 mutation (S649L) in cone-rod dystrophy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2404.
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To describe the clinical and genetic findings in a patient with a cone-rod dystrophy and a homozygous sequence variant (NM_001145849.1:c.1946C>T (p.Ser649Leu)) in the PROM1 gene.
Over 300 patients, with a variety of inherited retinopathies, attending the Research Foundation at the Royal Victoria Eye and Ear Hospital, Dublin, were recruited prospectively and clinically characterized. Patients underwent assessment of best-corrected visual acuity, Goldmann perimetry, Lanthony D15 colour vision testing, slit-lamp biomicroscopy, ISCEV clinical standard electroretinography, colour and autofluorescence fundus photography and spectral-domain optical coherence tomography. Next generation sequencing (NGS) of 201 candidate genes was performed.
A sequence variant was detected in the PROM1 gene, c.1946C>T, (S649L) in a patient with a severe cone-rod dystrophy phenotype. No suspicious sequence changes were observed in any other candidate genes. The proband was a 31-year-old Indian female of Portuguese descent. She was homozygous for the mutation. Her unaffected parents were each heterozygous. The patient had an early-onset history of severe retinal degeneration which initially compromised her central vision. She was given a diagnosis of Stargardt Disease at age 5 years. Her vision continued to deteriorate and she developed nystagmus. Her visual acuity was reduced to hand movements in both eyes. The fundal examination revealed macular pigmented atrophy and nasal bone spicule pigmentation.
The PROM1 gene codes for prominin1, found on evaginations of the photoreceptor epithelium and may have a role in maintaining an appropriate lipid concentration within the plasma membrane. The homozygous PROM1 mutation c.1946C>T (S649L) has been documented previously in a case of cone-rod dystrophy but dismissed due to the discovery of the same homozygous mutation in an apparently unaffected control (Littink et al, 2010). We report a second, independently ascertained patient with a similar phenotype who is homozygous for the same PROM1 sequence variant.<br /> While we will continue to genotype this patient in an attempt to identify a definitive disease-associated gene mutation, our identification of a second patient with a cone-rod dystrophy phenotype and the homozygous PROM1 mutation, c.1946C>T, (S649L) is intriguing and adds to the suspicion that this particular mutation may, in fact, be pathogenic.
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