Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
The association between RNF4 (HGNC:10067) and Prader-Willi syndrome (MONDO:0008300) is currently supported by limited genetic evidence. Several case‐series and multi‐patient studies designed to evaluate candidate imprinted genes in subjects with Prader-Willi syndrome included RNF4 in their gene panels (PMID:28554868, PMID:17262171). However, no direct RNF4 pathogenic variants or definitive segregation in families have been reported. Consequently, while these studies suggest that RNF4 might be a potential contributor when evaluating the complex genetic architecture of this imprinting disorder, the overall gene‐disease association remains modest.
Genetic evidence is constrained by the absence of clearly reported coding alterations in RNF4; instead, RNF4 was screened alongside well‐established imprinted genes such as SNURF/SNRPN. The genetic data thus far have not demonstrated recurrent or founder variants in RNF4, and familial segregation supportive of a causative role is lacking (PMID:28554868).
In contrast, the functional studies provide moderate support for a mechanistic role. Multiple studies have robustly characterized RNF4 as a SUMO‐targeted ubiquitin ligase with critical functions in regulating SUMOylated substrates (PMID:16387868, PMID:23550137). Although these experimental data do not directly demonstrate a role for RNF4 in Prader-Willi syndrome, they establish a plausible biological foundation for how altered RNF4 activity might influence cellular pathways relevant to the syndrome.
The integration of the genetic and experimental findings suggests that RNF4’s inclusion in candidate diagnostic panels for Prader-Willi syndrome remains investigational. There is additional evidence from high-throughput and functional assays that exceeds the minimum ClinGen threshold; however, the direct clinical impact of RNF4 mutations is yet to be proven.
Key take‑home sentence: While robust functional insights into RNF4’s role in SUMO signaling support biological plausibility, the gene’s direct contribution to Prader-Willi syndrome remains limited and warrants further dedicated investigation to inform clinical decision‑making.
Gene–Disease AssociationLimitedCandidate gene studies in PWS cohorts included RNF4 (PMID:28554868, PMID:17262171) without direct pathogenic variants or robust segregation data. Genetic EvidenceLimitedNo direct coding variants or recurrent mutations in RNF4 have been identified in affected individuals; evidence is limited to its inclusion in multi-gene panels, lacking definitive genetic causation. Functional EvidenceModerateExperimental studies consistently demonstrate RNF4’s critical role in SUMO-mediated ubiquitination (PMID:16387868, PMID:23550137), suggesting a plausible mechanism even though a direct link to the PWS phenotype is yet to be established. |