FREM1 (FRAS1-related extracellular matrix 1) is an extracellular matrix protein essential for craniofacial and multi-organ development. Functionally, FREM1 mediates epidermal adhesion and epithelial structure maintenance during embryonic development 1. Mechanistically, FREM1 expression in cranial neural crest cells is regulated by Sonic hedgehog (Shh) signaling during midfacial morphogenesis, with FREM1 capable of inducing neural crest cell proliferation in a concentration-dependent manner 2. Additionally, FREM1 and its splice variant TILRR modulate NF-κB inflammatory signaling pathways 3. Homozygous recessive FREM1 mutations cause Manitoba-oculotrichoanal (MOTA) syndrome, characterized by eyelid malformations, aberrant hairlines, bifid nasal tips, and gastrointestinal anomalies 4, and bifid nose with anorectal and renal anomalies (BNAR) 5. FREM1-deficient mice exhibit microphthalmia, cryptophthalmos, congenital diaphragmatic hernia, renal agenesis, and rectal prolapse, with genetic interactions involving GATA4 and SLIT3 1. Heterozygous mutations have been associated with trigonocephaly type 2, though recent evidence suggests heterozygous deletions alone may not cause isolated trigonocephaly 67. FREM1 genetic variants also influence HIV-1 susceptibility through inflammatory pathway modulation 3.