Abstract: Objective  To investigate the clinical phenotypic characteristics and molecular genetic mechanisms of proximal symphalangism（ SYM1）， to analyze the potential pathogenic mechanisms of novel heterozygous variants in the NOG gene， and to expand its mutational spectrum. Methods  Two pediatric patients clinically diagnosed with SYM1 were enrolled. Their clinical data and family histories were collected. Whole-exome sequencing（ WES） was performed to identify candidate variants， followed by Sanger sequencing for familial co-segregation analysis. The pathogenicity of the identified variants was evaluated through population databases， in silico prediction tools， and cross-species conservation analysis， and classified according to the guidelines of the American College of Medical Genetics and Genomics （ACMG）. Results Both patients presented with proximal interphalangeal joint fusion in the hands and feet， with one case additionally exhibiting talipes varus deformity. WES identified two previously unreported de novo heterozygous variants in the NOG gene： c.106G>A （p.Ala36Thr） and c.609_610delinsTT （p.Arg204Trp）. These variants were absent from population databases and were not detected in the parents， consistent with de novo occurrence. Multiple predictive tools suggested potential pathogenicity， and the affected residues were highly conserved across species. According to ACMG criteria， the variants were classified as “likely pathogenic” and“ pathogenic”， respectively. Conclusion This study reports two novel heterozygous variants in the NOG gene and establishes their association with SYM1， thereby further expanding the mutational spectrum of this gene. The findings highlight the critical role of the NOG/BMP signaling pathway in joint differentiation and tissue remodeling， providing a theoretical basis for molecular diagnosis and personalized treatment of related congenital malformations.

Key words: Proximal symphalangism, &emsp, NOG gene, &emsp, Novel heterozygous mutation, &emsp, Whole-exome sequencing