HYLS1 is a centriolar protein essential for ciliogenesis and centriole structural integrity 1. The protein functions by stabilizing the centriolar microtubule wall through recruitment of inner scaffold proteins, a process dependent on its interaction with CEP120 1. HYLS1 specifically promotes triplet microtubule assembly by physically trapping the C-terminal tail of β-tubulin (TUBB), thereby initiating incomplete microtubule formation critical for centriole biogenesis 2. HYLS1 mutations cause hydrolethalus syndrome (HLS), a lethal autosomal recessive ciliopathy characterized by severe midline brain malformations, hydrocephalus, polydactyly, micrognathia, and lung defects 3. The most common HLS-associated mutation is a missense variant (D211G) that disrupts normal protein localization and centriole function 4. Disease pathogenesis involves loss of centriole integrity that prevents ciliogenesis in multiple tissues 1. Beyond classical HLS, HYLS1 variants have been identified in Joubert syndrome patients, expanding the ciliopathy spectrum associated with this gene 5. The tissue-specific manifestations reflect differential reliance on cilia-dependent functions across organ systems, with notable involvement of neuronal, renal, and ocular tissues 5.