Table 1

Rare monogenic forms of ID linked to mutations of components or regulators of the ubiquitin pathway

GeneProteinDiseaseGenetic abnormalitiesReferences
ASXL3Component of the Polycomb repressive deubiquitination (PR-DUB) complexBainbridge–Ropers syndrome, BRS (OMIM 615485) and ASDDe novo truncating mutations in BRS and missense mutations in ASDBainbridge et al. (2013); De Rubeis et al. (2014)
CUL4BScaffolding protein stabilizing cullin RING E3 ligaseXLID (OMIM 300304)Missense mutationsWang et al. (2013); Zou et al. (2007)
HECW2E3 ubiquitin ligase HECW2Neurodevelopmental disorder with hypotonia, seizures, and absent language, NDHSAL (OMIM 617268)Missense mutationsHalvardson et al. (2016)
HERC1E3 ubiquitin ligase HERC1Macrocephaly, dysmorphic facies, and psychomotor retardation, MDFPMR (OMIM 617011)Missense and frameshift mutationsAggarwal et al. (2016); Nguyen et al. (2016); Ortega-Recalde et al. (2015)
HERC2E3 ubiquitin ligase HERC2Syndrome of ID, autism, and variable neurological deficits (OMIM 615516)Missense mutationsPuffenberger et al. (2012)
HUWE1HECT, UBA, and WWE domain containing 1, E3 ubiquitin protein ligaseTurner type, XLID
(OMIM 309590)
Microduplications, missense mutationsFroyen et al. (2008); Moortgat et al. (2018)
MAGEL2E3 ubiquitin ligase enhancerPrader–Willi syndrome, PWS (OMIM 176270) and Schaaf–Yang syndrome, SHFYNG (OMIM 615547)Interstitial deletions and maternal uniparental disomy in PWS; truncating mutations in SHFYNGTacer and Potts (2017)
MID2Member of the TRIpartite motif (TRIM) family of RING E3 ligasesXLID (OMIM 300928)Missense mutationGeetha et al. (2014)
OTUD6BMember of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymesIntellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, IDDFSDA (OMIM 617452)Truncating and missense mutationsSantiago-Sim et al. (2017)
PLAAUbiquitin binding protein phospholipase A2 activating proteinNeurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, NDMSBA (OMIM 617527)Missense mutationsFalik Zaccai et al. (2017); Hall et al. (2017)
RLIMRNF12 E3 ubiquitin ligaseTonne–Kalscheuer syndrome, XLID (OMIM 300978) Missense mutationTønne et al. (2015)
TRIM50Member of the TRIpartite motif (TRIM) family of RING E3 ligasesWilliam–Beuren syndrome, WBS (OMIM 194050)Microdeletion on chr. 7q11.23Micale et al. (2008)
TRIP12Member of the HECT domain E3 ubiquitin ligases familyID with or without ASD (OMIM 6177520)CNVs, missense, frameshift, splicing mutationsZhang et al. (2017)
UBE2AE2 ubiquitin conjugating enzyme E2AXLID type Nascimento
(OMIM 300860)
Truncating and missense mutationsBudny et al. (2010); Nascimento et al. (2006)
UBE3BE3 ubiquitin ligase E3BBlepharophimosis-ptosis-ID syndrome, BPIDS (OMIM 244450)Truncating mutationsBasel-Vanagaite et al. (2012)
USPX9Deubiquitinating enzyme FAF-XFemale-restricted X-linked non-syndromic mental retardation-99 (OMIM 300919)Truncating mutation and X-chr. deletionAu et al. (2017)
  • XLID: X-linked ID, CNV: copy number variation.