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!
PSMD12 haploinsufficiency underlies Stankiewicz-Isidor syndrome (STISS), an autosomal dominant neurodevelopmental and craniofacial disorder caused by loss-of-function variants in PSMD12 (HGNC:9557; Stankiewicz-Isidor syndrome). The overall clinical validity is classified as Strong, supported by multiple unrelated probands, familial segregation, and concordant functional studies.
Genetic evidence includes 30 unrelated individuals with STISS harboring heterozygous truncating or splice variants in PSMD12. Six patients from two families carried p.Arg289Ter or p.Tyr111Ter truncating alleles (PMID:39641441), and 24 additional probands exhibited unique truncating single-nucleotide variants or copy-number deletions involving PSMD12 (PMID:34906456). A representative recurrent allele is c.865C>T (p.Arg289Ter) (PMID:39641441).
Segregation data show inheritance of truncating alleles in multiple affected relatives across at least two families, consistent with autosomal dominant transmission and complete penetrance. At least four additional affected family members segregate pathogenic PSMD12 variants alongside probands, further reinforcing causality.
The phenotypic spectrum of STISS includes global developmental delay, intellectual disability, speech delay, craniofacial dysmorphisms, short stature, acne, oligodontia, and novel features such as cholesteatoma and ovarian teratoma. Congenital cardiac, renal, and preaxial limb anomalies are also reported, with variable expressivity among carriers.
Functional studies demonstrate that PSMD12 truncating variants cause proteasome dysfunction and perturb intracellular protein homeostasis. Patient peripheral blood mononuclear cells and PSMD12-knockdown HEK293T lines exhibit impaired proteasome activity and upregulation of type I interferon–stimulated genes (PMID:35080150). These data confirm haploinsufficiency as the pathogenic mechanism.
In summary, genetic and experimental evidence converge to define PSMD12 haploinsufficiency as a definitive cause of STISS. Further studies on genotype–phenotype correlations may refine management and diagnostic algorithms. Key Take-home: PSMD12 truncating variants should be sought in individuals with developmental delay and craniofacial anomalies, as identification enables precise diagnosis and family counseling.
Gene–Disease AssociationStrong30 unrelated probands, multi-family segregation, concordant functional data Genetic EvidenceStrong30 probands with truncating PSMD12 variants across multiple families; segregation evidence Functional EvidenceModerateProteasome dysfunction and type I IFN signature demonstrated in patient cells and knock-down models |