Human Gene Module / Chromosome 9 / RFX3

RFX3regulatory factor X3

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
11 / 12
Rare Variants / Common Variants
30 / 0
EAGLE Score
15.95
Strong Learn More
Aliases
-
Associated Syndromes
-
Chromosome Band
9p24.2
Associated Disorders
ADHD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
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
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RFX3 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating the patterning of prethalamus and ventral telencephalon Magnani D , et al. (2015) No -
3 Support Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder Tabet AC , et al. (2015) Yes -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 Recent Recommendation Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
6 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Recent recommendation - Harris HK et al. (2021) Yes ADHD
9 Support - Woodbury-Smith M et al. (2022) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Michiko Torio et al. (2023) Yes -
12 Support - Gareth Chapman et al. (2024) Yes -
Rare Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 25844147 Tabet AC , et al. (2015)
- - copy_number_loss De novo - Simplex 33658631 Harris HK et al. (2021)
c.215+2T>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.808C>T p.Gln270Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.421A>G p.Met141Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1844G>A p.Arg615His missense_variant Familial - - 28831199 Li J , et al. (2017)
c.549+5G>A - splice_site_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.1968+1G>A - splice_site_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.515T>G p.Leu172Arg missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.752A>G p.Tyr251Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.764G>C p.Arg255Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1523C>A p.Ala508Glu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.*47T>C - 3_prime_UTR_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1335dup p.Asp446ArgfsTer4 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
TG>T -408 frameshift_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.587G>A p.Gly196Glu missense_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.674T>C p.Phe225Ser missense_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.722T>G p.Leu241Trp missense_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.550C>G p.Leu184Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1148T>C p.Phe383Ser missense_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.1327C>A p.Leu443Ile missense_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.1523C>A p.Ala508Glu missense_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.1813A>G p.Ser605Gly missense_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.1831G>T p.Asp611Tyr missense_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.1684C>T p.Gln562Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1835_1836del p.Leu612TyrfsTer7 frameshift_variant De novo - - 28831199 Li J , et al. (2017)
c.584_586del p.Glu195del inframe_deletion De novo - Simplex 33658631 Harris HK et al. (2021)
c.1141C>G p.Gln381Glu missense_variant De novo - Simplex 37717291 Michiko Torio et al. (2023)
c.1704dup p.Trp569ValfsTer6 frameshift_variant De novo - Simplex 33658631 Harris HK et al. (2021)
c.1486_1487del p.Leu496AlafsTer7 frameshift_variant Familial - Multiplex 33658631 Harris HK et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

1/1/2021
1
icon
1

Score remained at 1

Description

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 ASPM 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).

Reports Added
[Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior2021]
1/1/2020
1
icon
1

Score remained at 1

Description

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 ASPM 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).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
4
icon
1

Decreased from 4 to 1

New Scoring Scheme
Description

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 ASPM 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).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2017
icon
4

Increased from to 4

Description

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 ASPM 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).

Krishnan Probability Score

Score 0.52090968313373

Ranking 1687/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99977327438413

Ranking 794/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.68771398014229

Ranking 1083/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.4209127593613

Ranking 1222/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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