EYS

The EYS (Eyes Shut Homolog) gene encodes a critical extracellular protein that supports photoreceptor structure and function in the retina, particularly within the ciliary axoneme of rods and cones. 

Mutations in EYS are a leading cause of autosomal recessive retinitis pigmentosa (arRP), resulting in progressive vision loss and making it a key target in the genetic evaluation of inherited retinal disorders.

What is EYS?

The EYS (Eyes Shut Homolog) gene encodes a large extracellular protein essential for photoreceptor stability in the retina. It is highly expressed in rods and cones, localizing primarily to the ciliary axoneme, a microtubule-based structure critical for photoreceptor function. 

Mutations in EYS are a leading cause of autosomal recessive retinitis pigmentosa (arRP), a degenerative retinal disorder.

Biological Role

EYS is necessary for maintaining photoreceptor integrity, particularly by stabilizing the ciliary axoneme in rods and cones. This structure is vital for the transport of proteins necessary for phototransduction. 

Loss-of-function mutations in EYS lead to progressive photoreceptor degeneration, resulting in night blindness, peripheral vision loss, and ultimately complete blindness.

Molecular Characteristics

Structurally, EYS contains various domains that suggest a role in cellular organization and stability. 

At least four isoforms of the EYS protein are expressed in the retina, with isoforms 2 and 3 also detected in the testis, indicating potential functional diversity.

Clinical Relevance

EYS genetic mutations are the most common cause of arRP, particularly in Asian and European populations.

• Prevalence: 5% in Dutch and Canadian populations, 18-23.5% in Japanese populations.
• Disease Onset: Symptoms typically appear in the third decade of life, with progressive vision loss.
• Phenotypic Variability: Although rods are primarily affected, some patients develop cone-rod dystrophy, indicating broader retinal involvement.

Current Research & Advances

Ongoing research into EYS mutations has led to its inclusion in retinal dystrophy genetic panels, aiding in early diagnosis and genetic counseling for affected families. However, gene therapy for EYS-related retinopathies presents challenges due to the gene’s large size, prompting ongoing research into new strategies for potential therapeutic delivery. 

Additionally, neuroprotective therapies and stem cell-based interventions are being explored to delay disease progression. 

For advanced cases, emerging technologies such as optogenetic therapies and retinal implants offer potential vision restoration strategies, providing hope for future treatment options.

Who Should Get EYS Tested?

The following groups of people may consider EYS genetic testing:

Target Populations

• Patients with progressive vision loss, particularly those with a family history of arRP.
• Individuals with early-onset night blindness and peripheral vision impairment.
• Patients with unexplained cone-rod dystrophy or suspected hereditary retinal dystrophies.

Indications for Testing

• Suspected autosomal recessive retinitis pigmentosa (arRP).
• Progressive peripheral vision loss with early rod dysfunction (confirmed by ERG).
• Patients with non-syndromic retinal dystrophies with no clear genetic diagnosis.

Risk Factors

• Genetic: Inheritance is autosomal recessive; those with a family history of EYS mutations have a higher risk.
• Ethnic Background: Higher prevalence in Japanese and European populations.
• Environmental/Lifestyle Factors: No known external risk factors, but UV protection and nutritional support may slow disease progression.

Age and Demographics

• Most commonly diagnosed between 30-50 years.
• Early-onset cases (~20s) often exhibit rapid progression.

Guidelines and Recommendations

Genetic testing for EYS mutations should be considered for all patients with suspected inherited retinal dystrophies.

Early screening in at-risk family members can help with early intervention and visual adaptation strategies.

Multidisciplinary management, including low vision specialists, genetic counselors, and retinal specialists, is essential for optimal patient care.

Test Procedure and Interpretation

Testing for EYS is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for EYS genetic testing are considered to be without mutations that can alter the activity of the EYS proteins.

Clinical Implications of Positive EYS Mutations

The clinical implications of a positive EYS mutation test result will vary by individual, although EYS mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of symptoms of early vision loss.

Patients or practitioners with questions about the clinical implications of EYS mutations should seek further assessment with a genetic counselor or expert. 

Order Genetic Testing

Click here to compare genetic test panels and order genetic testing for health-related SNPs.