International Journal of Molecular Sciences · 25 authors, 6 centres
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This study used whole-exome sequencing in 21 families with early-onset high myopia (EoHM) and identified 51 candidate genes, with most variants classified as variants of uncertain significance. The findings support a polygenic inheritance model where multiple genetic alterations cumulatively contribute to EoHM. Clinically, these results may improve genetic diagnosis and early intervention for children at risk of severe myopia and associated ocular complications.
**Background:** Early-onset high myopia (EoHM) is defined as a spherical refractive error exceeding –6.00 diopters or axial length greater than 26 mm occurring in children under 10 years of age. It increases the risk of cataracts, glaucoma, retinal detachment, and macular degeneration. While common myopia involves both environmental and genetic factors, EoHM is thought to have a stronger genetic component. Previous studies have identified some genes for non-syndromic EoHM, but many cases remain unexplained. This study aimed to identify new candidate genes using whole-exome sequencing (WES) in 21 families with EoHM.
**Methods:** A combined ophthalmological and genetic study was performed by the Multidisciplinary Unit of Ophthalmogenetics (UMOG) of La Paz University Hospital, approved by the ethics committee. Inclusion criteria were: (1) bilateral myopia with refractive error ≤−6 diopters in at least one eye with onset before age 10; (2) inconclusive result from a prior panel of 419 ophthalmology-related genes; (3) absence of syndromic phenotype; and (4) absence of corneal disease or other secondary causes of high myopia. A total of 63 individuals from 21 unrelated families were recruited, including 30 affected individuals aged 6 to 80 years. All probands and available relatives underwent complete ophthalmologic evaluation including best-corrected visual acuity, refraction, funduscopy, axial length measurement, retinography, and OCT. Genomic DNA from peripheral blood was sequenced using Nextera DNA Exome and xGen Exome Research Panel v2 on HiSeq4000 and NovaSeq6000 platforms. Bioinformatics analysis included alignment to GRCh37/hg19, variant calling with GATK, and annotation with SnpEff and multiple databases. Variants were filtered by quality, allele frequency (<0.02 in ExAC populations), and CADD score, then classified according to ACMG standards using Franklin by Genoox. Candidate genes were selected based on literature linking them to EoHM, high myopia, syndromes with myopia, or involvement in development/homeostasis of retina, choroid, or sclera.
**Key Results:** The cohort included 21 probands (33.33% female, 66.66% male) with mean spherical equivalent of −12.044 diopters in the right eye and −11.499 diopters in the left eye. Funduscopic examination showed diffuse chorioretinal atrophy in 38% of cases (alone or with other features), tessellated fundus in 9%, and normal findings in 33%. No significant association between severity and gender was found (Fisher's exact test p=0.6557). A total of 83 variants were identified as potentially involved in EoHM: 2 (3%) classified as pathogenic (P), 5 (6%) as likely pathogenic (LP), and 74 (91%) as variants of uncertain significance (VUS). The 74 VUS were located in 47 genes. Among these 47 genes, 19.15% are associated with pathologies that may manifest as high myopia without other clinical features, including genes linked to myopia (CPSF1, ZNF644, LRPAP1, PRIMPOL; 8.51%), Stickler syndrome (COL9A1, COL9A2, COL9A3; 6.38%), Marfan syndrome (FBN1; 2.13%), and congenital stationary night blindness (TRPM1; 2.13%). The remaining 80.85% of genes are associated with various other pathologies but are considered candidates due to their role in eye development. Most variants (83%) were missense mutations. The most frequently altered genes across families were HSPG2 (altered in 6 families) and CSMD1 (altered in 4 families). Other genes altered in two or more families included TRPM1, KDM6B, CACNA1F, LAMA1, COL9A3, LAMA5, THBS2, PCDH15, FRMPD1, AGRN, LRP1, USH2A, CPSF1, TSG101, FLRT3, and LTBP2. The study proposes 51 candidate genes in total: TRPM1, ARHGEF18, KDM6B, HSPG2, COL9A2, FBLN1, CACNA1F, CSMD1, ADAMTSL1, LAMA1, COL9A3, LAMA5, THBS2, THBS1, PCDH15, BMPR2, LRP2, MAP3K1, LAMA4, PLG, VASH1, PER3, COL11A1, FRMPD1, GLB1, COL9A1, AGRN, GRM6, LRP1, CNTN6, FRMD4B, USH2A, ALKBH5, CEP290, CPSF1, OPN4, MYOM1, ZNF644, CFH, ARHGEF15, TSG101, LRPAP1, FLRT3, MMP9, PRIMPOL, ABCA4, LAMA2, LTBP2, BICC1, CNTN4, and FBN1.
**Clinical Implications:** The identification of multiple VUS in each patient suggests that EoHM may follow a polygenic inheritance pattern with cumulative effects of several genetic alterations. The high proportion of VUS (91%) underscores the need for further functional studies to confirm pathogenicity. The study highlights the importance of WES in identifying candidate genes when targeted panel sequencing is inconclusive. Early genetic diagnosis could enable earlier monitoring and intervention for children at risk of severe myopia and its complications. The coordinated work of multidisciplinary teams is emphasized to enhance patient care and diagnosis. Future studies including larger cohorts, whole-genome sequencing, transcriptome analysis, and functional validation are needed to clarify the role of these candidate genes in EoHM.