Unveiling ocular developmental disorders through short-read whole-genome sequencing.

Area of Science:

• Ophthalmology
• Medical Genetics
• Genomics

Background:

• Congenital eye malformations are genetically diverse, with less than 50% of patients receiving molecular diagnoses.
• Current genetic testing methods, including targeted next-generation sequencing (NGS) panels and chromosomal microarray analysis (CGH-array), often fail to provide definitive diagnoses.

Purpose of the Study:

• To evaluate the diagnostic utility of short-read whole genome sequencing (WGS) in a cohort of families with congenital eye developmental disorders.
• To determine if WGS can identify pathogenic variants missed by conventional genetic testing.

Main Methods:

• Short-read whole genome sequencing (WGS) was performed on 100 families with eye developmental disorders.
• Patient cohorts included those with microphthalmia-anophthalmia spectrum (M/A), coloboma, anterior segment dysgenesis, congenital cataracts, and foveal hypoplasia.
• Previous genetic testing (NGS panels, CGH-array) results were reviewed.

Main Results:

• WGS identified likely pathogenic variants in 18 patients.
• Candidate variants of uncertain significance were found in an additional 9 patients.
• Fourteen variants identified by WGS would have been missed by conventional genetic panels or CGH-array.

Conclusions:

• Short-read WGS significantly enhances the diagnostic yield for congenital eye malformations.
• WGS is particularly valuable for patients who remain undiagnosed after standard genetic testing.
• Integrating WGS into genetic evaluations can improve diagnostic outcomes for ocular developmental disorders.