A study on genetic copy number variations reveals NLGN1 is over represented in primary angle closure glaucoma patients

Introduction: Primary angle closure glaucoma (PACG) is one of the leading causes of blindness worldwide with a complex genetic etiology. For complex genetic disorders, copy number variation (CNV) is anticipated to play an essential role in disease vulnerability. The impact of CNVs on PACG has not been studied yet. Methods: In India, ~30% of people show narrow angle but 0.5-1% of people actually develop PACG. To minimize heterogeneity, we performed a genome-wide CNV analysis between older (age ≥60 years) anatomically suspects (PACS) showing narrow angle <15° and PACG individuals having age ≤50 years to detect genetic factors responsible for glaucomatous neurodegeneration. Results: We identified a recurrent amplification involving the genomics region of NLGN1 in PACG. Subsequently, quantitative PCR validated increased NLGN1 copy number in PACG compared to PACS and controls. Integrative bioinformatics revealed NLGN1 's role in pathways associated with neurodegenerative and ocular diseases, its interactions with genes impacting glaucoma risk factors like intraocular pressure and optic nerve morphology, and regulatory genomic features in the amplified region potentially affecting NLGN1 expression. Discussion: The amplification may induce synaptic defects in retinal neurons or developmental abnormalities in visual pathways, precipitating neurodegeneration. The findings provide compelling evidence linking NLGN1 copy number gains to PACG pathogenesis, suggesting NLGN1 's potential relevance to glaucoma biology.