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JE Craig, NJ Marchbank, C Toomes, DL Healey, KM Rattray, M Toohey, P McCartney, AJ Churchill, CF Inglehearn, DA Mackey; Incomplete Penetrance in Large Autosomal Dominant Optic Atrophy Pedigrees . Invest. Ophthalmol. Vis. Sci. 2002;43(13):907.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The gene mutated in autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28 (OPA1) was recently identified. Estimates of penetrance for ADOA have varied considerably. The purpose of this study was to investigate penetrance in two large multi-generational pedigrees with established OPA1 mutations. Methods: Two large pedigrees with typical clinical features of ADOA were ascertained in South-Eastern Australia (ADOA Vic1, and ADOA Tas4). Linkage to OPA1 on chromosome 3q28 was confirmed. Identification of the responsible mutations in OPA1 enabled a formal study of penetrance by the attempted ascertainment of all mutation carrying individuals. Examples of incomplete penetrance were noted in each pedigree. Pedigree members were examined and findings documented (visual acuity, color vision, automated perimetry and stereo disc photos). Results: Clinical examination has been performed in 14 individuals carrying a 560-860 kb deletion encompassing the entire OPA1 gene in pedigree ADOA Vic1, and in 29 individuals carrying a 4bp deletion in exon 27, 2708del(TTAG) in pedigree ADOA Tas4. Combined results for Snellen visual acuity (VA) are presented for 43 mutation carriers. 11/43 (25.6%) had VA 20/20 or better in both eyes (mostly with normal color vision, automated perimetry and disc appearance). 22/43 (51.2%) maintained sufficient VA to hold a driving license. 30/43 (69.8%) had VA worse than 20/20 but better than or equal to 20/200. 2/43 individuals (4.7%) were legally blind (VA worse than 20/200). Conclusion: A significant percentage of carriers of OPA1 mutations are asymptomatic and have normal or better than average VA. We have observed slow progression with age. Ascertainment of all individuals in these pedigrees known to be affected has been completed. We expect penetrance levels to fall as further unaffected carriers are ascertained and are currently investigating the determinants of disease severity.
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