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Relevance to Autism

A de novo damaging missense variant and an inherited loss-of-function variant in the RFX3 gene were identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (De Rubeis et al., 2014; Krumm et al., 2015). A de novo loss-of-function variant and an inherited damaging missense variant in RFX3 were identified in Chinese ASD probands in Guo et al., 2017. Subsequent Transmission and De Novo Association (TADA) analysis in Guo et al., 2017 identified RFX3 as an ASD candidate gene, with a PTADA of 0.002128 in the Chinese ASD case-control cohort and a PTADA of 0.007677 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. A de novo deletion affecting exons 2-4 of the RFX3 gene has also been identified in a 13-year-old female patient presenting with a diagnosis of autism (Tabet et al., 2015). Deletion of Rfx3 in mice resulted in defects in right-left symmetry, malformation of the corpus callosum, and hydrocephalus (Magnani et al., 2015). Additional de novo loss-of-function and missense variants in this gene have since been identified in ASD probands from the SPARK cohort, the MSSNG cohort, and the Autism Sequencing Consortium (Feliciano et al., 2019; Satterstrom et al., 2020; Zhou et al., 2022); a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified RFX3 as a gene reaching study-wise significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X2, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating the patterning of prethalamus and...
Support
Integrating de novo and inherited variants in 42
ASD
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Support
Excess of rare, inherited truncating mutations in autism.
ASD
Support
Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.
ASD
Support
ASD, DD, epilepsy/seizures
Recent recommendation
Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior
ASD, DD, ID
ADHD
Recent Recommendation
Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN940R001 
 missense_variant 
 c.1523C>A 
 p.Ala508Glu 
 De novo 
  
  
 GEN940R002 
 frameshift_variant 
 TG>T 
 -408 
 Familial 
 Paternal 
 Simplex 
 GEN940R003 
 frameshift_variant 
 c.1835_1836del 
 p.Leu612TyrfsTer7 
 De novo 
  
  
 GEN940R004 
 missense_variant 
 c.1844G>A 
 p.Arg615His 
 Familial 
  
  
 GEN940R005 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN940R006 
 missense_variant 
 c.515T>G 
 p.Leu172Arg 
 De novo 
  
  
 GEN940R007 
 stop_gained 
 c.1684C>T 
 p.Gln562Ter 
 De novo 
  
 Simplex 
 GEN940R008 
 3_prime_UTR_variant 
 c.*47T>C 
  
 De novo 
  
 Simplex 
 GEN940R009 
 inframe_deletion 
 c.584_586del 
 p.Glu195del 
 De novo 
  
 Simplex 
 GEN940R010 
 missense_variant 
 c.722T>G 
 p.Leu241Trp 
 De novo 
  
 Simplex 
 GEN940R011 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN940R012 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN940R013 
 missense_variant 
 c.1831G>T 
 p.Asp611Tyr 
 De novo 
  
 Simplex 
 GEN940R014 
 frameshift_variant 
 c.1704dup 
 p.Trp569ValfsTer6 
 De novo 
  
 Simplex 
 GEN940R015 
 splice_site_variant 
 c.1968+1G>A 
  
 De novo 
  
 Simplex 
 GEN940R016 
 frameshift_variant 
 c.1486_1487del 
 p.Leu496AlafsTer7 
 Familial 
  
 Multiplex 
 GEN940R017 
 splice_site_variant 
 c.549+5G>A 
  
 De novo 
  
 Simplex 
 GEN940R018 
 missense_variant 
 c.1327C>A 
 p.Leu443Ile 
 De novo 
  
 Simplex 
 GEN940R019 
 missense_variant 
 c.674T>C 
 p.Phe225Ser 
 De novo 
  
 Simplex 
 GEN940R020 
 missense_variant 
 c.1148T>C 
 p.Phe383Ser 
 De novo 
  
 Simplex 
 GEN940R021 
 missense_variant 
 c.587G>A 
 p.Gly196Glu 
 De novo 
  
 Simplex 
 GEN940R022 
 missense_variant 
 c.1523C>A 
 p.Ala508Glu 
 De novo 
  
 Simplex 
 GEN940R023 
 missense_variant 
 c.1813A>G 
 p.Ser605Gly 
 De novo 
  
 Simplex 
 GEN940R024 
 missense_variant 
 c.550C>G 
 p.Leu184Val 
 Unknown 
  
  
 GEN940R025 
 missense_variant 
 c.764G>C 
 p.Arg255Pro 
 De novo 
  
 Simplex 
 GEN940R026 
 missense_variant 
 c.752A>G 
 p.Tyr251Cys 
 De novo 
  
 Simplex 
 GEN940R027 
 frameshift_variant 
 c.1335dup 
 p.Asp446ArgfsTer4 
 De novo 
  
  
 GEN940R028 
 stop_gained 
 c.808C>T 
 p.Gln270Ter 
 De novo 
  
  
 GEN940R029 
 splice_site_variant 
 c.215+2T>C 
  
 De novo 
  
  
 GEN940R030 
 missense_variant 
 c.421A>G 
 p.Met141Val 
 De novo 
  
  
 GEN940R031 
 missense_variant 
 c.1141C>G 
 p.Gln381Glu 
 De novo 
  
 Simplex 
  et al.  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
9
Deletion
 2
 
9
Deletion-Duplication
 14
 
9
Duplication
 3
 
9
Duplication
 7
 
9
Duplication
 3
 
9
Duplication
 2
 
9
Duplication
 4
 
9
Deletion
 3
 
9
N/A
 5
 
9
Deletion
 10
 
9
Deletion
 7
 
9
Deletion-Duplication
 13
 
9
Duplication
 3
 
9
Duplication
 1
 

No Animal Model Data Available

 

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