June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Phenotypic variability of WFS1 related eye disease
Author Affiliations & Notes
  • Sarah Hull
    Ophthalmology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, Auckland, New Zealand
    Ophthalmology, Auckland District Health Board, Auckland, Auckland, New Zealand
  • Leo Sheck
    Ophthalmology, Auckland District Health Board, Auckland, Auckland, New Zealand
  • Alec Hou
    Ophthalmology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, Auckland, New Zealand
  • Andrea L Vincent
    Ophthalmology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, Auckland, New Zealand
    Ophthalmology, Auckland District Health Board, Auckland, Auckland, New Zealand
  • Footnotes
    Commercial Relationships   Sarah Hull, None; Leo Sheck, None; Alec Hou, None; Andrea Vincent, None
  • Footnotes
    Support  Save Sight Society New Zealand
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1563. doi:
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      Sarah Hull, Leo Sheck, Alec Hou, Andrea L Vincent; Phenotypic variability of WFS1 related eye disease. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1563.

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

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Abstract

Purpose : Wolfram syndrome characterised by diabetes mellitus (DM), sensorineural hearing loss (SNHL), optic atrophy and diabetes insipidus arises from bi-allelic variants in WFS1. Less commonly, heterozygous variants are associated with a similar phenotype. In this retrospective, observational study, a group of patients with variants in WFS1 underwent detailed phenotypic analysis.

Methods : A series of 8 patients from 6 families were ascertained from the New Zealand Database of Inherited Retinal and Optic Nerve Disease. Targeted Sanger sequencing or next generation sequencing using an ocular gene panel were performed. Detailed phenotyping included retinal imaging, electrophysiology, neuroimaging and endocrine investigations.

Results : 8 patients (5 female, 3 male) from 6 families (2 Māori, 2 Asian. 1 Pasifika, 1 NZ European) were ascertained. Four families (6 patients) had likely pathogenic variants in WFS1 consistent with recessive disease in 3 and possible dominant disease in one. All 6 patients had optic atrophy with temporal>nasal disc pallor and marked nerve fibre layer thinning on optical coherence tomography. DM was identified in 5 of 6 patients (average age of onset 9 ± 4 years), 2 had SNHL, 2 had reduced fertility and one had diabetes insipidus. The patient with a heterozygous variant found by Sanger sequencing, had optic atrophy, DM, congenital SNHL, DM and premature ovarian insufficiency. Her initial presentation was with optic atrophy with very high blood sugars were identified as part of subsequent systemic investigations. She also had cortical blue dot cataract and persistent bilateral microcystic macular edema despite optimised glycemic control. It is possible that she has a second large copy number variant not identified by Sanger sequencing.
Two further probands had an identical variant (p.Val606Gly) of uncertain significance predicted to be damaging by multiple in silico tools, and with an allele frequency of 3.54 e-5 on gnomAD. This was homozygous in one patient with isolated extensive posterior chorioretinal atrophy onset in her 5th decade and heterozygous in a patient with optic atrophy, SNHL and impaired glucose tolerance onset in his 6th decade.

Conclusions : The phenotypic spectrum related to WFS1 variants is highly variable with only one patient in this series representing the full Wolfram spectrum. For patients presenting with optic atrophy, DM investigations are warranted.

This is a 2021 ARVO Annual Meeting abstract.

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