A rare case of fronto-nasal dystosis with multiple dysmorphic features: comprehensive genetic analysis using whole genome sequencing

Frontonasal dysostosis (FND) is a rare congenital disorder characterized by craniofacial abnormalities with diverse clinical characteristics. We report a four-year-old male with clinical characteristics related to frontonasal dysostosis, including hypertelorism, enlarged nostrils, telecanthus, cryptorchidism, forehead abnormalities, calcaneovalgus deformity, and rocker-bottom foot. Trio whole genome sequencing identified a rare pathogenic variant (c.3487C > T; p. Arg1163Trp) in the ZSWIM6 gene affecting a conserved residue in the sin3-like domain and predicted to destabilize the protein structure. Additionally, structural variant analysis revealed 29 rare SVs involving genes including BMPR1B, ESCO2, CWC27, KCNH1, and NELL1, which have known roles in craniofacial and limb development. Pathway enrichment analysis highlighted disruption of BMP and Notch signaling pathways, both of which are crucial for embryonic morphogenesis. Phenotype-gene-based prioritisation confirmed an association with abnormal toe, long bone morphology, and upper limb morphology. Our case highlights the heterogeneous and multifactorial genetic basis of FND, suggesting ZSWIM6 and other candidate genes as potential contributors to the phenotypic spectrum.