FOXC1-related Axenfeld–Rieger spectrum secondary to 6p25 deletion with concomitant distal 13q duplication arising from a maternal balanced t(6;13) translocation

BACKGROUND: Anterior segment dysgenesis (ASD) encompasses a heterogeneous group of developmental disorders arising predominantly from disrupted neural crest cell migration and differentiation. We report an extremely rare case of FOXC1-related Axenfeld-Rieger spectrum associated with a dual chromosomal imbalance inherited through a maternal balanced translocation. CASE PRESENTATION: A 4-month-old female presented with bilateral corneal opacity, posterior embryotoxon, iridocorneal adhesions, early-onset glaucoma, and an atrial septal defect. By 18 months, additional features included dysmorphic facies, severe hypotonia, profound global developmental delay, failure to thrive, short stature, and sensorineural hearing impairment. GENETIC FINDINGS: Clinical exome sequencing identified no clinically relevant single-nucleotide variants. Copy number variation (CNV) analysis revealed a heterozygous 6p25 deletion (~2.8 Mb) encompassing FOXC1 and a concomitant distal 13q duplication (~14.15 Mb). Parental karyotyping confirmed a maternal balanced translocation, 46,XX,t(6;13)(p25;q22). The proband inherited a derivative unbalanced chromosome through adjacent segregation. FOXC1 haploinsufficiency explains the anterior segment phenotype, while the distal 13q duplication likely contributes to the severe systemic manifestations through a multigenic dosage effect. CONCLUSION: This case expands the phenotypic and genetic spectrum of FOXC1-related ASD beyond classical monogenic presentations and highlights the importance of CNV analysis and parental cytogenetic evaluation in syndromic anterior segment dysgenesis when sequencing-based variant analysis is non-diagnostic.