June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Detailed characterization of an inherited optic atrophy cohort demonstrates highly variable phenotypes and uncommon molecular associations
Author Affiliations & Notes
  • Andrea L Vincent
    Ophthalmology, FMHS, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
    Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand
  • Alec Lin Hou
    Ophthalmology, FMHS, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
  • Sarah Hull
    Ophthalmology, FMHS, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
    Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand
  • Leo Sheck
    Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand
  • Footnotes
    Commercial Relationships   Andrea Vincent, None; Alec Hou, None; Sarah Hull, None; Leo Sheck, None
  • Footnotes
    Support  Save Sight Society of New Zealand
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2404. doi:
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    • Get Citation

      Andrea L Vincent, Alec Lin Hou, Sarah Hull, Leo Sheck; Detailed characterization of an inherited optic atrophy cohort demonstrates highly variable phenotypes and uncommon molecular associations. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2404.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To describe the genotypic spectrum, and associated ocular and systemic phenotypes in a cohort of presumed inherited optic atrophy (OA) cases.

Methods : Probands with presumed inherited optic atrophy were identified from the New Zealand Database of Inherited Retinal and Optic Nerve disease. For OPA1 and LHON mt DNA negative patients, mutational analysis of candidate genes OPA3, WFS1, TMEM126A, ACO2, RTNPI41, and CISD2 was undertaken by Sanger sequencing and high resolution melting analysis, or with a next generation sequencing panel. Clinical examination included comprehensive ocular examination and imaging, audiology, diabetic profiling and neurological phenotyping. Family members were recruited and examined if possible.

Results : Of 28 probands identified, molecular diagnosis was clearly achieved in 16, with 2 other equivocal findings. 10 probands had OPA1 mutations, with 18 affected family members in total. The spectrum of disease included isolated OA, non-penetrance, associated deafness, and Behr syndrome. Pathogenic WFS1 variants were seen in 4 probands – 2 compound heterozygotes, and 2 heterozygotes, with variable deafness, diabetes and ovarian insufficiency. Two siblings had biallelic ACO2 mutations, and one proband had a single ACO2 pathogenic variant. Another proband had biallelic RTN4IP1 mutations. A single pathogenic TMEM126A variant was present in one proband, with apparent dominant inheritance and non-syndromic optic atrophy. No variants in OPA3 or CISD2 were identified. Three clearly dominant families remain without a genetic diagnosis.

Conclusions : Pathogenic variants in OPA1 account for 30% of OA in this cohort, with significant variability in phenotype, including Behr syndrome in a child with biallelic OPA1 variants. WFS1-associated disease was more common than expected, with milder phenotypes in the Wolfram-like syndrome with a single WFS1 variant not observed. Although ACO2 and TMEM126A are rare and reported with syndromic autosomal recessive OA, it is feasible a single heterozygous change may manifest with a milder phenotype, as observed with WFS1.

This is a 2020 ARVO Annual Meeting abstract.

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