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<p>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 &gt; T; p. Arg1163Trp) in the <i>ZSWIM6</i> 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 <i>BMPR1B</i>, <i>ESCO2</i>, <i>CWC27</i>, <i>KCNH1</i>, and <i>NELL1</i>, 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 <i>ZSWIM6</i> and other candidate genes as potential contributors to the phenotypic spectrum.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月26日

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  • Sanjukta Sahoo,
  • Deepak Jena,
  • Mamuni Swain,
  • Bhawna Gupta,
  • Ravi Kant Narayan,
  • Prabhas Ranjan Tripathy,
  • Arun Kumar S,
  • Manisha Rajanand Gaikwad,
  • Sunil Kumar Raghav

摘要

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.