Variable Penetrance and Expressivity of Autosomal Dominant Optic Atrophy

Abstract

Abstract: : Purpose: Autosomal Dominant Optic Atrophy (ADOA), due to the OPA1 gene on chromosome 3, is the most common form of inherited optic atrophy. There appears to be great variability in the level of visual loss from ADOA. We wished to evaluate the penetrance and expressivity in large Australian ADOA pedigrees with mutations in OPA1. Methods: We evaluated four pedigrees (a total of 88 mutation carriers), Vic1 (19 mutation carriers) with a 560–860 kb deletion encompassing the entire OPA1 gene, Tas4 (31 mutation carriers) with a 4bp deletion in exon 27 2708del of OPA1, Vic13 (8 mutation carriers) with an exon19 mutation 1798G–T Glu600Stop in the gene, and NSW1 (30 mutation carriers) with 3 segregating base pair changes in exon 9 and another in exon 11. Clinical examination included assesment of visual acuity, colour vision, Humphrey 24–2 visual field and stereophotography of fundi. DNA (from buccal swab or blood sample) was obtained for OPA1 mutation screening by SSCP, gene sequencing, deletion mapping or FISH. Results: In the four large ADOA pedigrees, 20% of mutation carriers had visual acuity of 6/6 or better. Only 11% were legally blind. In addition, high and low risk branches of pedigrees were identified. Conclusions: The variable penetrance and expressivitiy of ADOA associated with OPA1 mutations, indicates a role for genetic modifiers and environmental factors.

Keywords: genetics • clinical (human) or epidemiologic studies: prevalence/incidence • low vision