TBL1XR1 is an F-box-like protein that functions as an integral component of the N-CoR corepressor complex, mediating recruitment of the 19S proteasome to nuclear receptor-regulated transcription units 1. The protein plays an essential role in transcription activation by facilitating proteasomal degradation of N-CoR complexes, enabling cofactor exchange and transcriptional switching 2. TBL1XR1 coordinates with SMRT/HDAC3 repressor complexes and interacts with key transcriptional regulators including BACH2 and BCL6, thereby controlling cell-fate decisions in B cell development 1. Pathogenic TBL1XR1 variants cause intellectual developmental disorder and autism spectrum disorder, with de novo mutations contributing to approximately 1% of sporadic autism cases 3. The mutant protein skews B cell differentiation toward abnormal immature memory cells while impairing plasma cell formation, driving extranodal lymphomagenesis through cyclic germinal center reentry 1. TBL1XR1 mutations are recurrent in diffuse large B-cell lymphoma, particularly in the MCD-like genetic subtype associated with poor prognosis and activated B-cell origin 4. Clinically, TBL1XR1 mutations in neurodevelopmental disorders manifest with global developmental delay, speech impairment, intellectual disability, hypotonia, and facial deformity 5. Additionally, TBL1XR1 mutations may predict favorable response to ibrutinib in CNS lymphoma 6.