RLIM – Tonne-Kalscheuer Syndrome

RLIM encodes the RING finger E3 ubiquitin ligase RNF12 and is causally implicated in Tonne-Kalscheuer syndrome (TOKAS), also classified as X-linked intellectual disability 61 ([MONDO:0010506]). TOKAS is an X-linked recessive multiple congenital anomaly disorder characterized by intellectual disability, variable dysmorphism and visceral malformations, notably congenital diaphragmatic hernia (HP:0000776). Female carriers are asymptomatic due to skewed X-chromosome inactivation, while hemizygous males manifest the full spectrum.

Antenatal exome analysis in six French families identified 11 previously unpublished fetal TOKAS cases, of which 9 of 11 presented with diaphragmatic hernia, differences in sex development and other malformations, establishing diaphragmatic hernia as a recurrent prenatal feature (PMID:38849204). These findings extend prior reports of 41 postnatal cases and underscore the recognizability of TOKAS at fetopathological examination.

Genetic evidence includes 52 affected males across nine unrelated pedigrees. In a three-generation Norwegian kindred, the missense variant c.1067A>G (p.Tyr356Cys) co-segregated with disease in four affected males (LOD 3.0), and no other shared rare X-linked variants were detected (PMID:25735484). Larger cohorts encompassing 84 individuals confirm pathogenic RLIM missense variants in 40 males with XLID and normal cognition in 44 heterozygous females (PMID:29728705).

The RLIM variant spectrum is exclusively missense, clustering in the RING finger and basic regulatory regions. A recurrent c.1831C>T (p.Arg611Cys) allele accounts for 66% of fetal TOKAS cases, and additional likely pathogenic variants include c.1262A>G (p.Tyr421Cys) associated with perinatal lethality from diaphragmatic hernia (PMID:38849204; PMID:33953269).

Functional assays demonstrate that patient-specific RLIM missense variants impair E3 ubiquitin ligase activity in vitro and fail to rescue rlim mutant zebrafish, consistent with severe loss-of-function (PMID:29728705). The p.Tyr421Cys variant shows reduced protein stability and ligase activity in embryonic stem cells (PMID:33953269), and RLIM-specific flow cytometry reporters confirm that p.Asn581Lys disrupts catalytic function (PMID:39482882).

Collectively, the genetic and experimental data converge on a loss-of-function mechanism whereby defective RLIM-mediated ubiquitination dysregulates LIM-domain transcriptional complexes and imprinted X-chromosome inactivation. No conflicting evidence has been reported.

Taken together, these data support a Definitive gene–disease association. RLIM sequencing should be included in diagnostic panels for congenital diaphragmatic hernia and X-linked intellectual disability; identification of pathogenic variants enables accurate genetic counseling and prenatal diagnosis.

References

• Journal of medical genetics • 2024 • Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective. PMID:38849204
• European journal of human genetics : EJHG • 2015 • Syndromic X-linked intellectual disability segregating with a missense variant in RLIM. PMID:25735484
• Molecular psychiatry • 2019 • Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder. PMID:29728705
• Scientific reports • 2021 • A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome. PMID:33953269
• HGG advances • 2025 • RLIM-specific activity reporters define variant pathogenicity in Tonne-Kalscheuer syndrome. PMID:39482882

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