ClinGen Dosage Sensitivity Curation Page

RAB39B

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
20159109 Giannandrea et al., 2010 (AJHG) reported two large families (details below) with X-linked intellectual disability (XLID) segregating with point mutations in the RAB39B gene. These mutations (nonsense and splice-site) are predicted to result in a loss-of-function (immunoblotting of HeLa cells transfected with each mutant cDNA did not detect any mutant protein) and were not seen in 150 adult European male controls. In pedigree of family X, figure 1D, 2 affected in second generation and 4 affected individuals in third generation segregating with intellectual disability (2 carrier females in first two generations). Sequence confirmed for a premature stop codon p.Y7X variant in exon 1 of the canonical transcript In pedigree of family MRX72, fig. 1E, multiple affected individuals (7 males) and carrier females (6, one deceased). Also sequence confirmed for a cryptic 5? splice donor site variant. Affected individuals reported with intellectual disability as well as autism spectrum disorders and seizures.
21076407 Vissers et al., 2010 analyzed 10 trios by WES for sequence variants associated with unexplained ID. A nonsense variant, p.Trp186X (Table 2), was identified in the RAB39B gene in proband of Trio 2 and determined the alteration was de novo.
23871722 To assess the clinical relevance of reported mutations in genes that have been implicated in monogenic X-linked intellectual disability (XLID), Piton et al., 2013 examined the prevalence of X chromosome mutations in the general population by studying 10,563 X chromosomes from the National Heart, Lung, and Blood (NHLBI) Exome Sequencing Project and systematically reassessed 106 XLID genes. Based on their scoring criteria, RAB39B was considered to be a confirmed XLID gene. The authors reported two loss of function variants, one a splice site change and the other a nonsense variant, Tyr7* (Supp Table 2) in the large cohort of individuals with XLID. Neither of these two variants are reported in gnomAD.

Haploinsufficiency phenotype comments:

Three independent RAB39B mutations, presumed to represent loss of function alleles, have been identified in cases of X-linked intellectual disability (additional new literature described below). Based on scoring criteria, this gene should receive a haploinsufficiency score of 3. However, it should be noted that focal deletions in the literature have not been described, and nullisomy of the region (including additional genes; see below) is suggested to result in male lethality. With consideration of the presumption of loss of function without focal deletions, the evidence of pathogenicity should be considered to be increasing. RAB39B is contained within a ~0.5 Mb region of Xq28 (the int22h-1/int22h-2-flanked region) that has been reported in association with increased risk for spontaneous abortion in females, suggesting this region may also be nullisomic lethal (see PMIDs 21984752, 9245997, 22429151). Females with deletions of this region have skewed X-inactivation. Of note, in gnomAD dataset, pLoF exp: 5.8, obs: 0, pLI = 0.83, HI on DECIPER = 21.7. These predictions somewhat in agreement and indicate moderate loss of function for this gene In gnomAD SV dataset, a 370kb deletion that includes 8 other RefSeq genes, including RAB39B, were observed in 2 individuals, no hemizygotes reported. additional literature on Parkinson relationship and RAB39B ? PMID: 31951675: In 2020 study by Gao et al, reported in the journal Movement disorder, case of a male individual hemizygous for the T168K. Authors showed that the T168K variant results in loss of RAB39B protein. And among individuals with idiopathic Parkinson Disease, RAB39B protein was significantly reduced in the prefrontal cortex ? PMID: 26739247: In 2016 study by Lochte et al in Parkinsonism Relat. Disord journal: As a caveat, RAB39B mutations in classic Parkinson disease patients without intellectual disability are rare and may not always show a convincing mutation in Parkinson disease patients ? PMID: 26399558 Mata et al in 2015 reported on a large pedigree segregating X-linked dominant Parkinson disease. The cohort contained 7 affected individuals, 5 males and 2 females; 2 of the 5 males had intellectual disability. All affected patients carried a missense mutation in the RAB39B gene Although a link between early onset Parkinsonism and variants in RAB39B have been described, as noted in the publications above; the clinical phenotype resulting from RAB39B alterations seems to demonstrate heterogeneity in the degree of intellectual disability with some patients not revealing convincing disease-causing variants. Additional studies towards pathogenicity and role of RAB39B variants in Parkinson disease is warranted.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

RAB39B is contained within a ~0.5 Mb region of Xq28 (the int22h-1/int22h-2-flanked region) that has been reported in association with XLID in males when duplicated (see PMIDs 21984752, 22659343, 23299923, 24357492), however focal duplications of RAB39B have not been reported. Vanmarsenille et al., 2013 (PMID 24357492) examined mRNA levels of four brain-expressed genes in the int22h-1/int22h-2-flanked region (BRCC3, VBP1, RAB39B, and CLIC2) in EBV-PBL cell lines from 5 controls versus 2 patients and found increased relative expression of all genes except CLIC2 in the patients. RAB39B overexpression studies in mouse hippocampal neurons showed branching and synapse formation phenotypes. The authors favor a pathogenic role for this gene in int22h-1/int22h-2 duplication carriers. As of May 2020, gnomAD SD reports 8 duplications about 154kb involving RAB39B and VBP1; 5 of them hemizygous in the healthy population. PMID: 27081496: A 2014 review article in Hum Genome Var cataloged duplications of the Xq28 region, with MECP2 being a well known gene linked to ID. Observed duplications also included neighboring regions, which included RAB39B with no focal duplications mentioned for this gene. And since many segmental duplications located in this region, the observed interstitial duplications are recurrent.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.