Early onset X-linked female limited high myopia in three multigenerational families caused by novel mutations in the ARR3 gene

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Abstract

This study describes the clinical spectrum and genetic background of high myopia caused by mutations in the ARR3 gene. We performed an observational case series of three multigenerational families with high myopia (SER≤−6D), from the departments of Clinical Genetics and Ophthalmology of a tertiary Dutch hospital. Whole-exome sequencing (WES) with a vision-related gene panel was performed, followed by a full open exome sequencing. We identified three Caucasian families with high myopia caused by three different pathogenic variants in the ARR3 gene (c.214C>T, p.Arg72*; c.767+1G>A; p.?; c.848delG, p.(Gly283fs)). Myopia was characterized by a high severity (<−8D), an early onset (<6 years), progressive nature, and a moderate to bad atropine treatment response. Remarkably, a female limited inheritance pattern was present in all three families accordant with previous reports. The frequency of a pathogenic variant in the ARR3 gene in our diagnostic WES cohort was 5%. To conclude, we identified three families with early onset, therapy-resistant, high myopia with a female-limited inheritance pattern, caused by a mutation in the ARR3 gene. The singular mode of inheritance might be explained by metabolic interference due to X-inactivation. Identification of this type of high myopia will improve prompt myopia treatment, monitoring, and genetic counseling.

Original languageEnglish
Pages (from-to)380-388
Number of pages9
JournalHuman Mutation
Volume43
Issue number3
DOIs
Publication statusPublished - Mar 2022

Bibliographical note

Funding Information:
This study was supported by the following foundations: Netherlands Organization for Scientific Research (NWO); Grant 91617076 (VJMV) and Grant 91815655 (CCWK), and European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme Grant 648268 (CCWK). The funding organizations had no role in the design or conduct of this research. They provided unrestricted grants.

Funding Information:
This study was supported by the following foundations: Netherlands Organization for Scientific Research (NWO); Grant 91617076 (VJMV), The Erasmus MC Fellowship 2020 (VJMV), and Grant 91815655 (CCWK), and European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme Grant 648268 (CCWK). The funding organizations had no role in the design or conduct of this research. They provided unrestricted grants.

Publisher Copyright:
© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC

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