Autosomal Dominant Optic Atrophy: Penetrance and Expressivity in Patients With OPA1 Mutations

doi:10.1016/j.ajo.2006.12.038

American Journal of Ophthalmology

Volume 143, Issue 4, April 2007, Pages 656-662.e1

https://doi.org/10.1016/j.ajo.2006.12.038 Get rights and content

Purpose

We identified families with autosomal dominant optic atrophy (ADOA), determined the number and type of OPA1 mutations, and investigated the phenotypic variation and penetrance in ADOA Australian pedigrees.

Design

Cross-sectional genetics study.

Methods

Probands were identified on the basis of characteristic clinical features of ADOA. We screened the OPA1 gene using single-strand conformational polymorphism, heteroduplex analysis (SSCP/HA), or by direct sequencing. Penetrance for pedigrees in which a mutation of OPA1 had been identified was calculated initially using all recruited individuals, and subanalysis was performed using only those families for which there was total recruitment of siblings.

Results

A total of 406 patients from 17 pedigrees were recruited, and OPA1 mutations were identified in 11/17 (65%) of these. The mean age at clinical examination was 38.2 ± 19.9 years (median age, 35 years; range, four to 83 years). The median best-corrected visual acuity in OPA1-mutation carriers was 20/70 (range, 20/16 to hand movements [HM]). The penetrance in Australian ADOA pedigrees in the families with complete sibling recruitment was 82.5%. On the other hand, overall penetrance for all individuals harboring an OPA1 mutation was 88%.

Conclusions

OPA1 mutations were identified in 11/17 (65%) of the ADOA pedigrees in this study. The penetrance in our cohort was lower than originally described (82.5% vs 98%) but higher than some recent studies since the availability of genotyping. It is anticipated that this figure would be even lower as more asymptomatic individuals are identified. There are likely to be other genetic and environmental modifiers influencing disease penetrance.

Section snippets

Subject Recruitment

Patients were recruited from different clinical centers across Australia. The study conformed to the tenets of the Helsinki Declaration, and informed consent was obtained from all participants.

Mutation Screening

DNA was collected using either buccal swab or venipuncture and was extracted using either the Puragene (Gentra Systems, Minneapolis, Minnesota, USA) or Amersham Biosciences Nucleon BACC kits (Amersham Biosciences, Piscataway, New Jersey, USA), respectively. Mutations in the OPA1 gene were screened using

Mutation Spectrum

Four hundred six affected and unaffected individuals from 17 ADOA pedigrees were recruited. OPA1 mutations had previously been reported in five of these pedigrees,13, 23 thus, only additional family members were screened for the relevant mutation. The remaining 12 pedigrees underwent full mutation screening of OPA1. Mutations were identified in six (50%) of these pedigrees. Four of these mutations had previously been reported; however, three novel mutations were identified in two families:

Discussion

In this study, a total of 17 ADOA pedigrees were recruited; however, OPA1 mutations were only identified in 11 (65%) of these. This is similar to other reports on OPA1 mutations in ADOA.10, 13, 14, 15, 23, 24, 25 These families are likely to harbor mutations in unidentified genes, and we are currently extending the number of subjects from the remaining pedigrees without OPA1 mutations to ensure suitable power for linkage analysis.15, 25, 26, 27

The clinical findings of marked intra- and

Amy C. Cohn, MBBS (Hons), is currently an Ophthalmology Registrar at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. She completed her Master of Medicine in 2005 in the area of Autosomal Dominant Optic Atrophy. Dr Cohn was awarded the International Congress of Eye Research “Young Investigator” Award in 2004 for her work in this field. Dr Cohn interests are clinical genetics of the optic nerve and retina.

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Original articleAutosomal Dominant Optic Atrophy: Penetrance and Expressivity in Patients With OPA1 Mutations

Purpose

Design

Methods

Results

Conclusions

Section snippets

Subject Recruitment

Mutation Screening

Mutation Spectrum

Discussion

Ophthalmology

Ophthalmology

Am J Ophthalmol

J Biol Chem

FEBS Lett

J Biol Chem

Cell

Mol Genet Metab

Genet Med

Linkage analysis in dominant optic atrophy

Am J Hum Genet