IMPG2-related maculopathy
IMPG2-related maculopathy
Purpose: to investigate the phenotype, variability, and penetrance of IMPG2-related maculopathy.
Design: retrospective observational case series.
Methods: clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling.
Results: a total of 25 individuals with a mono-allelic IMPG2 variant were included, 5 of whom were relatives of patients with IMPG2-associated retinitis pigmentosa. A distinct maculopathy was present in 17 individuals (median age, 52 years; range, 20-72 years), and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best-corrected visual acuity (BCVA) was ≥20/50 in the better eye (n = 15), and 5 patients were asymptomatic. Longitudinal observation (n = 8, up to 19 years) demonstrated stable maculopathy (n = 3), partial/complete resorption (n = 4) or increase (n = 1) of the subretinal material, with overall stable vision (n = 6). No manifest maculopathy was observed in 8 individuals (median age, 58 years; range, 43-83 years; BCVA ≥20/25), all were identified through segregation analysis. All 8 individuals were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. A total of 18 different variants were detected, 11 of them truncating. Molecular modeling of 5 missense variants [c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C, and c.3193G>A] supported the hypothesis that these have a loss-of-function effect.
Conclusions: mono-allelic IMPG2 variants may result in haploinsufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related retinitis pigmentosa may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually associated with moderate visual impairment.
32-42
Birtel, Johannes
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Caswell, Richard
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De Silva, Samantha R.
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Herrmann, Philipp
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Rehman, Salwah
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Lotery, Andrew J.
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Mahroo, Omar A.
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Michaelides, Michel
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Webster, Andrew R.
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MacLaren, Robert E.
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Charbel Issa, Peter
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February 2024
Birtel, Johannes
d9b4d729-36be-430c-8ae2-ae47e878853d
Caswell, Richard
c0bf3503-41ac-4388-a6ec-35769c1b587c
De Silva, Samantha R.
78f45184-7d56-4a3f-91f7-af63ebfd95ec
Herrmann, Philipp
23f9d9fe-9ba4-4124-9872-6bd5f0e6e461
Rehman, Salwah
22e42e4a-006c-40e0-8468-124d68b7f7c2
Lotery, Andrew J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Mahroo, Omar A.
e4b59d99-86b4-419a-8dae-f674278c9dc1
Michaelides, Michel
a76e6d62-f966-4d81-ac30-dea7612d98b3
Webster, Andrew R.
f368f0ff-61ea-4d58-8616-89addba40268
MacLaren, Robert E.
c7a2f458-a7b1-4b96-b88e-d376c90ec059
Charbel Issa, Peter
d6c64772-b7a8-43a6-8bb8-350b4f5acdb6
Birtel, Johannes, Caswell, Richard, De Silva, Samantha R., Herrmann, Philipp, Rehman, Salwah, Lotery, Andrew J., Mahroo, Omar A., Michaelides, Michel, Webster, Andrew R., MacLaren, Robert E. and Charbel Issa, Peter
(2024)
IMPG2-related maculopathy.
American Journal of Ophthalmology, 258, .
(doi:10.1016/j.ajo.2023.10.002).
Abstract
Purpose: to investigate the phenotype, variability, and penetrance of IMPG2-related maculopathy.
Design: retrospective observational case series.
Methods: clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling.
Results: a total of 25 individuals with a mono-allelic IMPG2 variant were included, 5 of whom were relatives of patients with IMPG2-associated retinitis pigmentosa. A distinct maculopathy was present in 17 individuals (median age, 52 years; range, 20-72 years), and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best-corrected visual acuity (BCVA) was ≥20/50 in the better eye (n = 15), and 5 patients were asymptomatic. Longitudinal observation (n = 8, up to 19 years) demonstrated stable maculopathy (n = 3), partial/complete resorption (n = 4) or increase (n = 1) of the subretinal material, with overall stable vision (n = 6). No manifest maculopathy was observed in 8 individuals (median age, 58 years; range, 43-83 years; BCVA ≥20/25), all were identified through segregation analysis. All 8 individuals were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. A total of 18 different variants were detected, 11 of them truncating. Molecular modeling of 5 missense variants [c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C, and c.3193G>A] supported the hypothesis that these have a loss-of-function effect.
Conclusions: mono-allelic IMPG2 variants may result in haploinsufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related retinitis pigmentosa may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually associated with moderate visual impairment.
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IMPG2_related_maculopathy_Manuscript_revision_final_for_Andrew_Lotery_
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Accepted/In Press date: 1 October 2023
e-pub ahead of print date: 6 October 2023
Published date: February 2024
Additional Information:
Funding Information:
Funding/Support: This work was supported by the Dr. Werner Jackstädt Foundation, Wuppertal, Germany (Grant S0134-10.22 to J.B.), and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and the NIHR BRC at Moorfields Eye Hospital and the UCL Institute of Ophthalmology. O.A.M. is supported by the Wellcome Trust ( 206619/Z/17/Z ). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The sponsor and funding organization had no role in the design or conduct of this research. Financial Disclosures: All authors report no financial disclosures or conflicts of interest. All authors attest that they meet the current ICMJE criteria for authorship.
Publisher Copyright:
© 2023 Elsevier Inc.
Identifiers
Local EPrints ID: 486397
URI: http://eprints.soton.ac.uk/id/eprint/486397
ISSN: 0002-9394
PURE UUID: afee5c95-5651-4348-9547-a985cff32fdc
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Date deposited: 19 Jan 2024 17:35
Last modified: 18 Mar 2024 02:57
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Contributors
Author:
Johannes Birtel
Author:
Richard Caswell
Author:
Samantha R. De Silva
Author:
Philipp Herrmann
Author:
Salwah Rehman
Author:
Omar A. Mahroo
Author:
Michel Michaelides
Author:
Andrew R. Webster
Author:
Robert E. MacLaren
Author:
Peter Charbel Issa
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