Genetic and clinical landscape ofARR3-associated MYP26: the most common cause of Mendelian early-onset high myopia with a unique inheritance

Abstract

AimsTo elucidate genetic background of early-onset high myopia (eoHM) and characteristics of ARR3-associated MYP26.MethodsVariants in 14 genes reported to contribute to eoHM, including ARR3, were selected from exome sequencing data set and classified into different categories following American College of Medical Genetics and Genomics guidelines based on in silico prediction, associated phenotypes, confirmation and cosegregation analysis. The available clinical data of individuals were summarised.ResultsPathogenic and likely pathogenic variants in three of 14 genes were identified in 52 of 928 families with eoHM, including 29 in ARR3, 22 in OPN1LW and 1 in LRPAP1. For ARR3, 24 pathogenic variants (16 truncation and 8 missense) were identified in 66 women and 12 men, in whom 64 women and 4 men had eoHM by X-linked female-limited inheritance. Refraction ranged from −5.00 to −28.75 diopter (−12.58±4.83). Mild-to-moderately reduced cone responses were recorded in 76.9% (10/13) of patients with electroretinogram recordings. Most patients (75.9%, 41/54) had mild myopic fundus changes (C0 to C1). Genotype–phenotype analysis suggested that the myopic retinopathy degree was correlated with age and the variant’s nature. Peripheral retinal degeneration was observed in 38.5% (5/13) patients using wide-field examinations.ConclusionThis study reveals ARR3 as the most frequently implicated gene for Mendelian eoHM. Truncations and highly scored missense variants in ARR3 are pathogenic. Myopia due to ARR3 mutations is transmitted in X-linked female-limited inheritance, manifests with mild cone impairment and slowly progresses to pathologic myopia. Identification of the most common cause for Mendelian eoHM provides a valuable starting point into the molecular mechanism of myopia.

WITHDRAWN: Novel splicing variants in ARR3 gene cause the female- limited early-onset high myopia

“…Variants in the ARR3 gene have been linked to X-linked female-limited eoHM, which is a rare disorder predominantly affecting females and exhibiting a femalelimited inheritance pattern [2,[5][6][7]. Similar inheritance patterns have been observed in cases of epilepsy and cognitive impairment associated with variants in the PCDH19 gene [8].…”

“…Both genetic and environmental factors contribute to the development of eoHM. While environmental factors such as excessive reading or computer use, lack of outdoor activities, and insu cient lighting can contribute to myopia development [4], genetic factors are considered to be the primary drivers of eoHM [5].…”

Unique Haplotypes in OPN1LW as a Common Cause of High Myopia With or Without Protanopia: A Potential Window Into Myopic Mechanism

“…The partial splicing-effect haplotype (LVAVA) in the L-M hybrid gene lead to eoHM with colorblindness due to changes in spectral sensitivity. In combination with our previous analysis, OPN1LW was found not only to be the top two most frequently implicated genes for nonsyndromic monogenic eoHM (2.4%), second only to ARR3 (3.1%), 18 but might be among the top five common causative genes for syndromic monogenic eoHM when patients with colorblindness were included. This is the first time that such unique haplotypes in a well-known gene have been implicated as one of the most common causes of nonsyndromic eoHM.…”

“… 15 , 17 One of our recent studies suggested that LVAVA haplotypes in OPN1LW may be the second most common cause of eoHM after ARR3 . 18 …”

Variants in HNRNPH1 are associated with high myopia in humans and ocular coloboma in zebrafish

“…Variants in these genes can only explain about 6% of eoHM. 20 Except for these, eoHM may present as a key sign for other ocular or systemic diseases, and variants in genes responsible for such diseases contribute to about one-fourth of eoHM. 21,22 Therefore, the exact genetic defects for most high myopia are awaited to be discovered.…”