Identification of a Novel AMER1 Variant and Craniofacial Phenotypic Spectrum in Osteopathia Striata with Cranial...

Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked dominant genetic disorder mediated by variants in the AMER1 gene, characterized primarily by generalized skeletal sclerosis and striated changes. However, research on its craniofacial phenotypes has long been fragmented, lacking systematic pedigree construction and basis for precise management. This study integrates a 16-year follow-up patient carrying a novel AMER1 frameshift variant (c.966delT; p.Phe322Leufs*3) with 66 literature-confirmed patients, and systematically analyzes craniofacial phenotypic characteristics and genetic associations using Spearman correlation analysis, two-step clustering, and gene function prediction. The results show that orofacial clefts have the highest incidence (72%), with synergistic associations between retained deciduous teeth and impacted permanent teeth; two-step clustering identified four heterogeneous "genetic abnormality-phenotype" subtypes, with DNA/protein functional status as the core factor; it confirms that c.966delT is a pathogenic de novo variant, mediating Wnt pathway abnormalities as the core mechanism of phenotypes, and proposes a multidisciplinary management strategy. This study is the first to establish a quantitative pedigree and subtype classification for OSCS craniofacial phenotypes, deepening the understanding of molecular mechanisms and providing key basis for precise diagnosis, stratified intervention, and prognosis improvement.