Genomic Copy Number Variants Associated With Strabismus and Amblyopia in the All of Us Research Program.

PURPOSE: To identify rare and common copy number variants (CNVs) associated with strabismus and amblyopia.

METHODS

Case-control association study using structural variant calls from short-read whole-genome sequencing from the All of Us Research Program, including 1224 adults with strabismus, 564 with amblyopia (152 with both), and controls (95,175 for strabismus; 95,319 for amblyopia). Autosomal CNVs were identified using the GATK-SV pipeline. After instituting quality control measures, CNVs present in ≥20 affected individuals were divided into rare (<1% population frequency) and common (>1% population frequency). CNVs were manually verified in Integrative Genomics Viewer. In an independent analysis, we examined three intergenic duplications previously associated with strabismus to assess whether the findings could be replicated.

RESULTS

One rare and three common CNVs were associated with amblyopia: a rare intronic deletion in MDGA2, an intronic duplication in CAMK2D, and intronic deletions in COG1 and KMT2C. Three rare and 2 common CNVs were associated with strabismus: rare intronic deletions in PCDH15, GTF2H1, and NKAIN3, a common intronic deletion in TRANK1, and a common intronic duplication in GRK5. Implicated genes predominantly affect neuronal and synaptic function, including modulation of postsynaptic potential, retrograde transport, glutaminergic synaptic transmission, and calcium-mediated signaling. GRK5 interacts with CXCR4, a chemokine receptor critical for axon guidance of the oculomotor nerve. The previously identified chr4 duplication was also significantly associated with strabismus in the AoURP dataset, replicating previous findings.

CONCLUSIONS

CNVs are an additional source of genetic risk for strabismus and amblyopia and highlight synaptic and neurodevelopmental pathways as central to etiology.