The purpose of this study was to explore the genetic and clinical features of nanophthalmos with secondary angle-closure glaucoma (NSACG) in a Chinese cohort. This was a prospective cross-sectional study of 157 eyes from 88 Chinese patients with NSACG. The participants underwent ocular and systemic examinations and whole-exome sequencing. The main outcome measures were pathogenic genetic variants, axial length (AL), refractive spherical equivalent (SE), vitreous chamber depth (VCD), white-to-white (WTW), radius of corneal curvature (flat and steep K: K1 and K2), anterior chamber depth (ACD), lens vault (LV), lens thickness (LT), extent of angle closure, anterior segment crowding value, retinal nerve fiber layer (RNFL) thickness, central subfield thickness (CST) in macular, cup-to-disc ratio (C/D), mean defect in visual field, and onset age of angle-closure glaucoma (ACG). Seventy-eight variants (51.14%) were identified in 45 patients, including 20 in PRSS56 (44.44%) and 14 in MFRP (31.11%) with autosomal recessive (AR) inheritance, 8 in MYRF (17.78%), and 3 in TMEM98 (6.6%) with autosomal dominant (AD) inheritance. Individuals with genetic diagnosis were associated with shorter AL, higher SE, larger K1 and K2, shallower ACD, greater angle closure extent, larger LT/AL, shorter VCD, and higher incidence of retinal detachment. Compared with AR cases, patients with AD showed younger ACG onset, longer AL, lower SE, smaller K1 and K2, longer VCD, thinner CST of the macula, and more severe visual field defects. Among Chinese patients with NSACG, PRSS56 and MFRP were the predominant AR variants, whereas MYRF and TMEM98 were the main AD variants. Genetic diagnosis exhibited shorter AL and a more crowded anterior segment, leading to accelerated glaucoma progression. The faster glaucoma progression in AD cases highlights the need for early intervention.