Predominance and clustering of splice-site variants in Koreans with IMPG2-associated retinopathy: implications for haploinsufficiency and loss of function as disease mechanisms.

PURPOSE: To investigate the genetic and phenotypic spectrum of IMPG2-associated retinopathy in a Korean population.

METHODS

This retrospective multicenter study included patients with genetically confirmed IMPG2-associated retinopathy from four institutions in Korea. Comprehensive clinical features, including visual acuity, fundus appearance, and OCT findings were analyzed. Genetic testing was performed using targeted next-generation sequencing panels or whole-exome sequencing. The identified variants were classified according to ACMG guidelines to determine their pathogenicity.

RESULTS

Fourteen patients (11 males, 3 females; mean age, 41.4 ± 22.6 years) were included. Thirteen exhibited bilateral involvement. Clinical diagnoses comprised adult-onset vitelliform macular dystrophy (n = 7), retinitis pigmentosa (n = 6), and atypical macular dystrophy characterized by subtle, multifocal photoreceptor alterations (n = 1). Splicing variants at the exon 7-8 junction (c.828+1G>A, c.829-2_829-1delAG) and a splice acceptor variant at exon 9 (c.909-2A>T) were identified in 12 of 14 patients (85.7%), with c.828+1G>A being the most frequent (8/14, 57.1%). 84.2% of the identified variants and 92.9% of the patients harbored loss-of-function mutations, including splicing, frameshift, and nonsense variants.

CONCLUSION

Loss-of-function of IMPG2, including haploinsufficiency, appears to play a major role in IMPG2-associated retinopathy. The predominance and clustering of splice-site variants around the exon 7-8 junction may reflect a founder effect and regional sequence susceptibility.