Abstract
Hemizygous variants in the RLIM gene, which is located on chromosome Xq13, cause Tønne-Kalscheuer syndrome (TOKAS). This X-linked recessive disorder is characterized by intellectual disability (ID), global developmental delay, behavioral impairment, gait disturbances, minor facial anomalies, congenital diaphragmatic hernia, skeletal and urogenital abnormalities, including hypogenitalism, micropenis, and cryptorchidism. In this study, we report on a novel, likely pathogenic RLIM variant in a proband, the clinical phenotype of which is consistent with a diagnosis of TOKAS. Whole-exome sequencing (WES) was performed on a genomic DNA (gDNA) sample of the proband to identify the disease-causing variant. Validation and segregation analysis were performed by Sanger sequencing of the proband’s and his mother’s gDNA samples. Computational analysis and protein structure modelling were applied to assess the possible influence of the variant on protein function. A novel missense variant NM_016120.4:c.1721T > A, NP_057204.2:p.(Ile574Asn) in the RLIM gene was identified by the analysis of WES data. Segregation analysis revealed the asymptomatic mother to be a carrier of the familial missense variant, and a highly skewed X chromosome inactivation pattern was observed in this study. The altered residue was determined to be at the interaction interface between E3 ubiquitin ligase RLIM and E2 ubiquitin-conjugating enzymes. The findings provided in this study suggest that the affected residue Ile574 could alter the interactions of the RING domain with the E2 ubiquitin-conjugating enzymes and therefore could influence the ubiquitin-mediated protein regulation pathways. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12887-025-06194-3.