RLIM is an E3 ubiquitin ligase encoded on chromosome X that negatively regulates LIM homeodomain transcription factors by mediating ubiquitination and degradation of LIM cofactors LDB1 and LDB2. The protein also targets other substrates including the telomeric protein TERF1 and the pluripotency factor ZFP42/REX1, the latter function being critical for X-chromosome X in female embryos. RLIM achieves substrate-specific targeting through chrX recruitment via a basic region motif at gene promoters, enabling precise control of developmental gene expression 1. RLIM variants cause Tonne-Kalscheuer syndrome (TOKAS), an X-linked intellectual disability disorder characterized by developmental delay, craniofacial abnormalities, and in severe cases, perinatal lethality from congenital anomalies 2. Hemizygous males with RLIM missense or protein-truncating variants present with intellectual disability, distinctive behavioral features, and occasional seizures 3. Duplications of Xq13.2-q13.3 encompassing RLIM cause a milder neurocognitive phenotype in males with increased RLIM protein abundance and reduced levels of the RLIM substrate MDM2 4. RLIM also functions in Sonic hedgehog signaling during cerebellar development and medulloblastoma progression through stabilization of the ubiquitin ligase RNF220 5. Recent evidence suggests RLIM variants associate with reduced human lifespan through pathways enriched for cancer susceptibility 6. Flow cytometry-based RLIM-specific reporters enable experimental determination of variant pathogenicity, accelerating resolution of variants of uncertain significance in TOKAS 7.