Clinical Spectrum and Molecular Characteristics of Inherited Ocular Diseases in a Cohort of Pediatric Patients With Infantile Nystagmus Syndrome

Abstract

Purpose: Infantile nystagmus syndrome (INS), the most prevalent form of nystagmus in children, often indicates underlying ocular and neurological conditions. Genetic assessment plays a crucial role in clinical management, genetic counseling, and access to emerging gene-based therapies. This study aims to characterize the clinical and genetic landscape of inherited ocular diseases (IODs) in children with INS.

Methods: We retrospectively analyzed clinical and genetic data from 205 unrelated pediatric patients with INS enrolled in an IRB-approved nystagmus registry (2010-2024). All underwent next-generation sequencing (NGS) with targeted gene panels to detect pathogenic variants.

Results: The cohort comprised 117 males and 88 females (mean [SD] age, 8.85 [10.37] years). The most common INS-associated IODs included albinism (32%), Leber congenital amaurosis (LCA) (14%), and achromatopsia (14%). Genetic testing achieved a definitive diagnosis in 85 of 205 patients, yielding a molecular diagnostic rate of 41.5%. A total of 83 pathogenic and likely pathogenic variants were identified across 30 genes. The seven most frequently disease-causing genes-TYR, CNGB3, RPGR, GPR143, ABCA4, OCA2 and FRMD7-accounted for 65% of the genetically solved cases. Additionally, eight genes associated with LCA (AIPL1, CABP4, GUCY2D, IMPDH1, NMNAT1, RDH12, PRPH2, and RPGRIP1) contributed to 15% of these cases.

Conclusions: This study underscores the utility of NGS in diagnosing INS-associated IODs, providing essential insights for targeted interventions and identifying patients as candidates potentially eligible for ongoing gene-based therapy clinical trials.

Figure 1.

Clinical phenotypic spectrum in the genetically solved cohort with INS and INS-associated ocular conditions.

Figure 2.

Genetic findings and molecular diagnostic rate of targeted NGS in patient cohort with INS. Variants were detected in 85% of the patients. Based on variant classification, the pathogenic mutations were determined to cause diseases in 42% of the patients. The percentages are calculated over the total number of patients who underwent genetic testing. Insert: Pie chart showing the spectrum of variant types among all detected genes.

Figure 3.

Types of gene variants and prevalence of disease-associated causative genes identified in the genetically solved INS cohort. (A) Pie chart showing the distribution of all the gene variants underlying INS or its associated conditions according to their types. (B) Prevalence of disease-associated genes harboring causative variants in patients with INS.

Figure 4.

Most frequent variants identified in TYR- and CNGA3-/CNGB3-associated probands in genetically solved cohort. (A) Histogram showing the most frequent TYR variants. (B) Histogram of occurrence of the most recurrent CNGA3, CNGB3 and ATF6 variants.

Figure 5.

Most frequently found variants in the genetically solved cohort. (A) Bar graph showing the most frequently found variants in RPGR-associated probands. (B) Bar graph showing the most frequently found variants in ABCA4-associated probands. (C) Bar graph showing the most frequently found variants in GRP143-associated probands. (D) Bar graph showing the most frequently found variants in FRMD7-associated probands.

Figure 6.

Inheritance patterns and distribution of mutated genes in the genetically solved probands. (A) Percentage of inheritance patterns based on molecular diagnosis. Data derived from 85 genetically solved probands out of 205 genetically tested patients. (B–D) The prevalence and relative contribution of causative genes implicated in autosomal recessive (B), autosomal dominant (C), and X-linked (D) forms.