PLCB4 (phospholipase C beta 4) is a key enzyme in G-protein coupled receptor signaling pathways that catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to produce second messengers diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) 1. The enzyme functions as a direct effector in the endothelin-1-DLX5/DLX6 signaling pathway, which is critical for mandibular specification and craniofacial development 1. PLCB4 is expressed in multiple tissues including brain, retina, and skin, with tissue-specific splice variants identified 2. Disease-causing mutations in PLCB4 result in auriculocondylar syndrome (ACS), a rare craniofacial malformation characterized by distinctive 'question mark' ears, micrognathia, and mandibular condyle hypoplasia 13. These mutations disrupt the catalytic site and cause functional loss, leading to reduced DLX5 and DLX6 expression and resulting in a homeotic transformation where mandibular structures adopt maxillary characteristics 1. The syndrome shows incomplete penetrance and variable expressivity, with homozygous loss-of-function mutations causing more severe phenotypes including respiratory and gastrointestinal dysfunction 4. PLCB4 has also been implicated in oncogenic signaling in uveal melanoma and pigmentation regulation 56.