Abstract
PURPOSE: The purpose of this study was to identify pathogenic variants associated with congenital bony nasolacrimal duct obstruction (bony CNLDO) and to clarify genotype-phenotype correlations. METHODS: In this single-center retrospective case study, children with clinically confirmed bony CNLDO and their relatives underwent detailed ophthalmic, systemic examinations, orbital computed tomography (CT), and maxillofacial magnetic resonance imaging (MRI). Whole-exome sequencing (WES) was performed on peripheral blood samples. Bioinformatics tools were utilized to predict variant pathogenicity, and classifications were performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Thirty-two participants were included in this study, comprising six families and seven sporadic cases. WES identified 8 novel FGF10 variants, including 6 missense mutations (c.598C>G, c.316T>G, c.395T>C, c.316T>C, c.327C>G, and c.332T>G), one intronic splicing mutation (c.429+2T>A), and one heterozygous deletion at chromosome 5p12 encompassing the FGF10 gene. Two sporadic cases had no identifiable pathogenic variants. All patients with FGF10 variants exhibited syndromic aplasia of lacrimal and salivary glands (ALSGs) phenotype characterized by bony CNLDO, punctal anomalies, and hypoplasia of lacrimal, parotid, and submandibular glands. Three novel IGSF3 variants were also identified including two missense mutations (c.2872G>C and c.2531G>A) and one nonsense mutation (c.2416G>T). In contrast, individuals carrying IGSF3 variants showed isolated bony CNLDO with normal glandular morphology. CONCLUSIONS: Bony CNLDO is predominantly a monogenic disorder involving FGF10 or IGSF3. FGF10 mutations are associated with syndromic, multi-gland hypoplasia, whereas IGSF3 mutations result in isolated bony CNLDO. These findings enhance understanding of the genetic heterogeneity and genotype-phenotype correlations underlying bony CNLDO, with real-world implications for genetic diagnosis and counseling.