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

• Published in: Human mutation Vol. 43; no. 3; pp. 380 - 388
• Main Authors: Mazijk, Ralph, Haarman, Annechien E.G., Hoefsloot, Lies H., Polling, Jan R., Tienhoven, Marianne, Klaver, Caroline C.W., Verhoeven, Virginie J.M., Loudon, Sjoukje E., Thiadens, Alberta A.H.J., Kievit, Anneke J.A.
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.03.2022; John Wiley and Sons Inc
• Subjects: Arrestins - genetics; Atropine; Cohort Studies; Female; Genes, X-Linked; Genetic counseling; genetics; Heredity; Humans; Mendelian; Mutation; Myopia; Myopia - diagnosis; Myopia - genetics; Pedigree; refractive error; syndromic myopia; Whole Exome Sequencing; myopia; Mendelian; genetics; refractive error; syndromic myopia; atropine
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.24327

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. This study describes the clinical spectrum and genetic background of high myopia caused by mutations in the ARR3 gene. A mutation in this gene causes high myopia with a female‐limited inheritance pattern, probably caused by metabolic interference due to X‐inactivation.