Posters
Presenting Author Academic/Professional Position
Nafiza Meher
Academic Level (Author 1)
Medical Student
Academic Level (Author 2)
Faculty
Academic Level (Author 3)
Faculty
Academic Level (Author 4)
Faculty
Academic Level (Author 5)
Faculty
Discipline Track
Biomedical Science
Abstract Type
Research/Clinical
Abstract
Strabismus and nystagmus are prevalent eye movement disorders that impair visual function and overall quality of life. Strabismus refers to the misalignment of the eyes, while nystagmus is involuntary oscillatory eye movements. Both may be isolated conditions or indicators of underlying ocular, neurological, or genetic causes. Although numerous genes have been associated with nystagmus related disorders, there is still much to be known regarding causes of idiopathic nystagmus. Strabismus, especially when occurring isolated, has no known genetic causes, hindering progress in early diagnosis and targeted management. This study utilizes next-generation whole-genome sequencing (WGS) to improve diagnostic outcomes, explore potential candidate genes for strabismus, and expand the known genetic architecture of nystagmus.
Participants were identified and enrolled through Boston Children’s Hospital patient databases. Eligible pediatric patients with a clinical diagnosis of strabismus or nystagmus and their biological parents were enrolled. If related family members with the condition existed, they were also enrolled. Cheek swab samples were collected and processed through GeneDx for whole-genome sequencing. Trio-based analysis (proband and both parents) was used to identify known pathogenic variants as well as potential novel candidate genes. Diagnoses were considered “solved” if the proband had a likely pathogenic variant that explained their clinical presentation. All solved findings were clinically validated and communicated to families.
38 families (151 individuals) have been enrolled in the strabismus cohort and 49 families (125 individuals) in the nystagmus cohort. Within the nystagmus group, 12 probands (24.5%) have received definitive genetic diagnoses, and 10 additional cases (20%) have strong candidate gene findings. The genes associated with solved cases include CACNA1F (n=3), FRMD7 (n=2), SLC38A8 (n=2), CNGA3, CNGB3, COL18A1, LRAT, and TYR. Of particular note is the discovery of a novel structural variant in CACNA1F, a gene associated with congenital stationary night blindness. The variant is a 380 base pair inverted duplication between exons 41 and 42. This duplication introduces a premature stop codon resulting in protein truncation and was found in a child with nystagmus, who had clinical presentation of congenital stationary night blindness. Interestingly, this variant also potentially explains the mother’s high myopia, despite her lack of other symptoms, illustrating possible incomplete penetrance or variable expressivity.
In the strabismus cohort, the gene MARK4 has emerged as a promising candidate, although further validation studies are underway. Unlike nystagmus, no single gene has previously been associated with isolated strabismus, making this a notable step toward understanding its genetic basis.
This study demonstrates the utility of whole-genome sequencing in diagnosing pediatric eye movement disorders and contributes to ongoing gene discovery. The identification of known and novel variants, particularly the complex CACNA1F structural variant, showcases WGS’s diagnostic advantage over traditional sequencing methods. Early and accurate diagnosis facilitates timely intervention, avoids unnecessary testing, and enables informed family counseling. Moreover, the identification of MARK4 as a potential gene for isolated strabismus highlights the importance of continued research. These findings lay the groundwork for future therapeutic strategies and improved clinical care for affected children and their families.
Presentation Type
Poster
Recommended Citation
Meher, Nafiza; Martinez Sanchez, Mayra; Altschwager Kreft, Pablo; Fulton, Anne; and Whitman, Mary C., "Genetic Analysis of Strabismus, Nystagmus, and Associated Disorders" (2025). Research Colloquium. 75.
https://scholarworks.utrgv.edu/colloquium/2025/posters/75
Included in
Genetic Analysis of Strabismus, Nystagmus, and Associated Disorders
Strabismus and nystagmus are prevalent eye movement disorders that impair visual function and overall quality of life. Strabismus refers to the misalignment of the eyes, while nystagmus is involuntary oscillatory eye movements. Both may be isolated conditions or indicators of underlying ocular, neurological, or genetic causes. Although numerous genes have been associated with nystagmus related disorders, there is still much to be known regarding causes of idiopathic nystagmus. Strabismus, especially when occurring isolated, has no known genetic causes, hindering progress in early diagnosis and targeted management. This study utilizes next-generation whole-genome sequencing (WGS) to improve diagnostic outcomes, explore potential candidate genes for strabismus, and expand the known genetic architecture of nystagmus.
Participants were identified and enrolled through Boston Children’s Hospital patient databases. Eligible pediatric patients with a clinical diagnosis of strabismus or nystagmus and their biological parents were enrolled. If related family members with the condition existed, they were also enrolled. Cheek swab samples were collected and processed through GeneDx for whole-genome sequencing. Trio-based analysis (proband and both parents) was used to identify known pathogenic variants as well as potential novel candidate genes. Diagnoses were considered “solved” if the proband had a likely pathogenic variant that explained their clinical presentation. All solved findings were clinically validated and communicated to families.
38 families (151 individuals) have been enrolled in the strabismus cohort and 49 families (125 individuals) in the nystagmus cohort. Within the nystagmus group, 12 probands (24.5%) have received definitive genetic diagnoses, and 10 additional cases (20%) have strong candidate gene findings. The genes associated with solved cases include CACNA1F (n=3), FRMD7 (n=2), SLC38A8 (n=2), CNGA3, CNGB3, COL18A1, LRAT, and TYR. Of particular note is the discovery of a novel structural variant in CACNA1F, a gene associated with congenital stationary night blindness. The variant is a 380 base pair inverted duplication between exons 41 and 42. This duplication introduces a premature stop codon resulting in protein truncation and was found in a child with nystagmus, who had clinical presentation of congenital stationary night blindness. Interestingly, this variant also potentially explains the mother’s high myopia, despite her lack of other symptoms, illustrating possible incomplete penetrance or variable expressivity.
In the strabismus cohort, the gene MARK4 has emerged as a promising candidate, although further validation studies are underway. Unlike nystagmus, no single gene has previously been associated with isolated strabismus, making this a notable step toward understanding its genetic basis.
This study demonstrates the utility of whole-genome sequencing in diagnosing pediatric eye movement disorders and contributes to ongoing gene discovery. The identification of known and novel variants, particularly the complex CACNA1F structural variant, showcases WGS’s diagnostic advantage over traditional sequencing methods. Early and accurate diagnosis facilitates timely intervention, avoids unnecessary testing, and enables informed family counseling. Moreover, the identification of MARK4 as a potential gene for isolated strabismus highlights the importance of continued research. These findings lay the groundwork for future therapeutic strategies and improved clinical care for affected children and their families.
