Early-Onset High Myopia Panel

Myopia is the condition in which distant objects appear blurry due to refractive error in the eye, also known as nearsightedness. High myopia refers to the severe form of this condition and is defined as a refractive error of at least -6.00. Early-onset high myopia is loosely defined, but generally considered to have an age of onset of <10 years old. While myopia in general is very prevalent (up to 90% in some populations), the more specific early-onset high myopia is still estimated with a prevalence of about 1% in 5 and 6-year-olds (Li et al. 2022. PubMed ID: 34989760).

Early-onset high myopia can occur either in isolation or as part of a syndrome such as Stickler syndrome or Ehlers-Danlos syndrome. While many, variable phenotypes can be associated with these syndromes, the myopia phenotype can be one of the earliest indications. Therefore, this panel is intended to serve as a differential diagnosis test for syndromic and non-syndromic high myopia.

Non-syndromic myopia, like many traits, is caused by a combination of environmental and genetics factors; however, early-onset high myopia is more likely to have an underlying genetic component (Li and Zhang. 2017. PubMed ID: 29386878). To date, over 100 genes have been associated with myopia as reviewed by Cai et al. (Cai et al. 2019. PubMed ID: 31472110). The most common genes with causative variants include ARR3, ZNF644, SLC39A5, CCDC111, and LEPREL1, with inheritance patterns of X-linked, autosomal dominant, and autosomal recessive. In addition, this panel includes many genes with variants known to cause primary ocular disorders such as glaucoma, retinal dystrophy, and congenital stationary night blindness which may first present with myopia. Many of these genes are involved in the expected pathways of lens, retina, and general eye development.

Syndromes that include the symptom of high myopia such as Stickler syndrome, Ehlers-Danlos syndrome, and Adams-Oliver syndrome are also inherited in every manner (X-linked, autosomal dominant, autosomal recessive). Causative variants have been found in genes with a wide variety of functions from collagen genes (COL2A1, COL11A1, etc.) to metalloendopeptidase genes (ADAMTS10, ADAMTS2, etc.; Flitcroft et al. 2018. PubMed ID: 29346494).

See individual gene summaries for information about the molecular biology of gene products and spectra of pathogenic variants.

To our knowledge, there have been no studies on the clinical sensitivity of a myopia gene panel. We expect this panel to perform similarly to other eye disorder panels with a test yield of ~20%. The general heritability of myopia has been calculated to be ~90%, indicating genetics plays a large role in the development of the condition (Hammond et al. 2001. PubMed ID: 11328732). However, this is likely to include complex (polygenic) inheritance of variants. The incidence of monogenic myopia is unknown.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Please note that this test does not provide 100% coverage of the purine-rich region of RPGR ORF15 which requires special-chemistry Sanger sequencing. Patients with a strong indication for a diagnosis in RPGR (X-linked inheritance, retinitis pigmentosa phenotype) are better suited for testing with X-linked retinitis pigmentosa (XLRP) panel, which includes sequencing of ORF15.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).