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Relevance to Autism

RBL2 was identified as an ASD candidate gene in Wilfert et al., 2021 based on the discovery of private likely gene-disruptive (LGD) variants in this highly constrained (pLI 0.99) gene that were exclusively transmitted to four ASD probands in three independent families. Exome sequencing in two siblings with severe intellectual disability, stereotypies and dysmorphic features in Brunet et al., 2020 had previously identified biallelic loss-of-function variants in RBL2, establishing this gene as a candidate gene for an autosomal recessive neurodevelopmental disorder; Samra et al., 2021 subsequently identified three patients carrying biallelic RBL2-truncating variants, all of whom presented with infantile hypotonia, severe developmental delay and microcephaly.

Molecular Function

Key regulator of entry into cell division. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases KMT5B and KMT5C, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Probably acts as a transcription repressor by recruiting chromatin-modifying enzymes to promoters. Potent inhibitor of E2F-mediated trans-activation, associates preferentially with E2F5. Binds to cyclins A and E. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. May act as a tumor suppressor.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Recent ultra-rare inherited variants implicate new autism candidate risk genes
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
RBL2 bi-allelic truncating variants cause severe motor and cognitive impairment without evidence for abnormalities in DNA methylation or telomeric function
DD
Support
Biallelic loss-of-function variants in RBL2 in siblings with a neurodevelopmental disorder
DD, ID
Stereotypy, epilepsy/seizures
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1276R001 
 frameshift_variant 
 c.2461del 
 p.Gln821SerfsTer3 
 Familial 
  
  
 GEN1276R002 
 frameshift_variant 
 c.524_527del 
 p.Lys175ThrfsTer42 
 Familial 
  
  
 GEN1276R003 
 frameshift_variant 
 c.2589_2593del 
 p.Leu864GlufsTer8 
 Familial 
  
  
 GEN1276R004a 
 stop_gained 
 c.556C>T 
 p.Arg186Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN1276R004b 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Multiplex 
 GEN1276R005 
 synonymous_variant 
 c.807C>T 
 p.Ser269%3D 
 De novo 
  
  
 GEN1276R006 
 synonymous_variant 
 c.1293C>T 
 p.Thr431%3D 
 De novo 
  
  
 GEN1276R007 
 splice_region_variant 
 c.1975+4A>G 
  
 De novo 
  
  
 GEN1276R008 
 frameshift_variant 
 c.2589_2593del 
 p.Leu864GlufsTer8 
 Familial 
 Paternal 
 Multiplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
16
Deletion
 1
 
16
Deletion-Duplication
 13
 

No Animal Model Data Available

 

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