AFF2AF4/FMR2 family, member 2
Autism Reports / Total Reports
15 / 21Rare Variants / Common Variants
44 / 1Aliases
AFF2, FMR2, FMR2P, FRAXE, MRX2, OX19Associated Syndromes
Fragile X syndromeChromosome Band
Xq28Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASDGenetic Category
Rare Single Gene Mutation, SyndromicRelevance to Autism
Rare mutations in the AFF2 gene have been identified with autism and ADHD (Abrams et al., 1997) as well as with X-linked intellectual disability (XLID) (Stettner et al., 2011) and developmental and speech delay (Sahoo et al., 2011). In addition, this gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, a rare mutation in the AFF2 gene has been identified with fragile X syndrome (Moore et al., 1999).
Molecular Function
This gene encodes a putative transcriptional activator that is a member of the AF4FMR2 gene family. This gene is associated with the folate-sensitive fragile X E locus on chromosome X. A repeat polymorphism in the fragile X E locus results in silencing of this gene causing Fragile X E syndrome. Fragile X E syndrome is a form of nonsyndromic X-linked mental retardation. Alternate splicing results in multiple transcript variants.
External Links
SFARI Genomic Platforms
Reports related to AFF2 (21 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Support | Fragile X syndrome with FMR1 and FMR2 deletion | Moore SJ , et al. (1999) | No | MR, Epilepsy |
| 2 | Support | Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion | Stettner GM , et al. (2011) | No | - |
| 3 | Support | Microdeletion of Xq28 involving the AFF2 (FMR2) gene in two unrelated males with developmental delay | Sahoo T , et al. (2011) | No | - |
| 4 | Support | Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism | Chahrour MH , et al. (2012) | Yes | - |
| 5 | Recent Recommendation | Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder | Mondal K , et al. (2012) | Yes | - |
| 6 | Support | Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study | Rauch A , et al. (2012) | No | Epilepsy, ASD |
| 7 | Support | Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE | Nava C , et al. (2012) | Yes | ID |
| 8 | Support | Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders | Lim ET , et al. (2013) | Yes | - |
| 9 | Support | Using whole-exome sequencing to identify inherited causes of autism | Yu TW , et al. (2013) | Yes | - |
| 10 | Support | Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing | Jiang YH , et al. (2013) | Yes | - |
| 11 | Support | Autism spectrum disorder: FRAXE mutation, a rare etiology | Correia F , et al. (2014) | Yes | - |
| 12 | Support | Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities | Zhang Y , et al. (2015) | No | - |
| 13 | Support | Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder | C Yuen RK et al. (2017) | Yes | - |
| 14 | Support | Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder | Du X , et al. (2018) | Yes | DD/ID |
| 15 | Support | Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder | Wang L et al. (2020) | Yes | - |
| 16 | Support | - | Chen S et al. (2021) | Yes | DD, ID |
| 17 | Support | - | Zou D et al. (2022) | No | - |
| 18 | Support | - | Hu C et al. (2022) | Yes | - |
| 19 | Support | - | Miyake N et al. (2023) | Yes | - |
| 20 | Support | - | Hu C et al. (2023) | Yes | - |
| 21 | Primary | Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressing FRAXE | Abrams MT , et al. (1997) | Yes | ADHD |
Rare Variants (44)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | copy_number_loss | - | - | - | 22065534 | Sahoo T , et al. (2011) | |
| - | - | copy_number_loss | De novo | - | - | 10424820 | Moore SJ , et al. (1999) | |
| - | - | copy_number_loss | Familial | Maternal | - | 22065534 | Sahoo T , et al. (2011) | |
| c.587T>C | p.Phe196Ser | missense_variant | Unknown | - | - | 35741772 | Hu C et al. (2022) | |
| c.1160C>A | p.Ser387Tyr | missense_variant | Unknown | - | - | 34800434 | Chen S et al. (2021) | |
| c.835C>T | p.Gln279Ter | stop_gained | Unknown | - | Unknown | 23352160 | Lim ET , et al. (2013) | |
| c.168+508T>C | - | intron_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.*8999G>C | - | 3_prime_UTR_variant | Unknown | - | Multiplex | 23092983 | Nava C , et al. (2012) | |
| c.3466-382C>T | - | intron_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.3518+343T>G | - | intron_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.1074+4192A>G | - | intron_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.1074+4824A>G | - | intron_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.*2338T>C | - | 3_prime_UTR_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.*2942T>A | - | 3_prime_UTR_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.*3206C>T | - | 3_prime_UTR_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.2141A>C | p.Asp714Ala | missense_variant | Familial | Paternal | - | 37007974 | Hu C et al. (2023) | |
| c.2780G>A | p.Arg927His | missense_variant | Unknown | - | Simplex | 23352163 | Yu TW , et al. (2013) | |
| c.1891C>T | p.Pro631Ser | missense_variant | De novo | - | Simplex | 36973392 | Miyake N et al. (2023) | |
| c.3893G>A | p.Arg1298His | missense_variant | De novo | - | Simplex | 36973392 | Miyake N et al. (2023) | |
| c.1017C>T | p.Leu339= | synonymous_variant | Unknown | - | Simplex | 22773736 | Mondal K , et al. (2012) | |
| c.1962T>C | p.Thr654= | synonymous_variant | Unknown | - | Simplex | 22773736 | Mondal K , et al. (2012) | |
| c.3088A>C | p.Ile1030Leu | missense_variant | De novo | - | Simplex | 22773736 | Mondal K , et al. (2012) | |
| c.1072C>A | p.Arg358= | synonymous_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.1323C>G | p.Thr441= | synonymous_variant | Unknown | - | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.230A>T | p.Asn77Ile | missense_variant | Familial | Maternal | Simplex | 35431806 | Zou D et al. (2022) | |
| - | - | copy_number_loss | Familial | Maternal | Multi-generational | 21739600 | Stettner GM , et al. (2011) | |
| c.391C>T | p.His131Tyr | missense_variant | Familial | Maternal | Simplex | 35431806 | Zou D et al. (2022) | |
| c.2509C>T | p.Arg837Cys | missense_variant | Familial | Maternal | Simplex | 30555518 | Du X , et al. (2018) | |
| c.1540C>T | p.Arg514Cys | missense_variant | Familial | Maternal | Simplex | 35431806 | Zou D et al. (2022) | |
| c.2009G>A | p.Arg670His | missense_variant | Familial | Maternal | Simplex | 35431806 | Zou D et al. (2022) | |
| c.2074C>G | p.Pro692Ala | missense_variant | Familial | Maternal | Simplex | 35431806 | Zou D et al. (2022) | |
| c.2458C>T | p.His820Tyr | missense_variant | Familial | Maternal | Simplex | 23020937 | Rauch A , et al. (2012) | |
| c.1979G>C | p.Ser660Thr | missense_variant | Familial | Maternal | Simplex | 22773736 | Mondal K , et al. (2012) | |
| c.2509C>T | p.Arg837Cys | missense_variant | Familial | Maternal | Simplex | 22773736 | Mondal K , et al. (2012) | |
| c.1640G>A | p.Gly547Asp | missense_variant | Familial | Maternal | Multiplex | 26544041 | Zhang Y , et al. (2015) | |
| c.2140G>A | p.Asp714Asn | missense_variant | Familial | Maternal | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.2780G>A | p.Arg927His | missense_variant | Familial | Maternal | Multiplex | 22773736 | Mondal K , et al. (2012) | |
| c.2483dup | p.Glu829ArgfsTer5 | frameshift_variant | Familial | Maternal | Simplex | 33023636 | Wang L et al. (2020) | |
| c.2539C>G | p.Pro847Ala | missense_variant | Familial | Maternal | Multiplex | 22511880 | Chahrour MH , et al. (2012) | |
| c.511dup | p.Ser171LysfsTer28 | frameshift_variant | Familial | Maternal | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.527_528del | p.Gly176AlafsTer26 | frameshift_variant | Familial | Maternal | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.3634G>A | p.Val1212Ile | missense_variant | Familial | Maternal | Multi-generational | 23849776 | Jiang YH , et al. (2013) | |
| c.-460_-458GCC(6_25) | - | trinucleotide_repeat_microsatellite_feature | Familial | Maternal | Simplex | 9034011 | Abrams MT , et al. (1997) | |
| c.-460_-458GCC(6_25) | - | trinucleotide_repeat_microsatellite_feature | Familial | Maternal | Simplex | 25035088 | Correia F , et al. (2014) |
Common Variants (1)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.1074+4388T>A;c.1086+4388T>A;c.96+4388T>A | - | intron_variant | - | - | - | 22773736 | Mondal K , et al. (2012) |
SFARI Gene score
1
High Confidence
Score Delta: Score remained at 1
criteria met
See SFARI Gene'scoring criteriaWe 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.
10/1/2020
1
1
Score remained at 1
Description
There is a well established role for AFF2 (aka FMR2) in FRAXE, an X-linked ID with variable presentation (reviewed in PMID 11246464), but it is unclear whether rates of autism are increased relative to a TD population (see PMIDs 9034011, 21739600, and 22065534 for case reports of FRAXE cases with autism).
10/1/2019
4
1
Decreased from 4 to 1
New Scoring Scheme
Description
There is a well established role for AFF2 (aka FMR2) in FRAXE, an X-linked ID with variable presentation (reviewed in PMID 11246464), but it is unclear whether rates of autism are increased relative to a TD population (see PMIDs 9034011, 21739600, and 22065534 for case reports of FRAXE cases with autism).
Reports Added
[New Scoring Scheme]1/1/2019
4
4
Decreased from 4 to 4
Description
There is a well established role for AFF2 (aka FMR2) in FRAXE, an X-linked ID with variable presentation (reviewed in PMID 11246464), but it is unclear whether rates of autism are increased relative to a TD population (see PMIDs 9034011, 21739600, and 22065534 for case reports of FRAXE cases with autism).
4/1/2017
4
4
Decreased from 4 to 4
Description
There is a well established role for AFF2 (aka FMR2) in FRAXE, an X-linked ID with variable presentation (reviewed in PMID 11246464), but it is unclear whether rates of autism are increased relative to a TD population (see PMIDs 9034011, 21739600, and 22065534 for case reports of FRAXE cases with autism).
Reports Added
[Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.2012] [Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder.2012] [Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.2012] [Using whole-exome sequencing to identify inherited causes of autism.2013] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Autism spectrum disorder: FRAXE mutation, a rare etiology.2014] [Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.2013] [Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressing FRAXE.1997] [Microdeletion of Xq28 involving the AFF2 (FMR2) gene in two unrelated males with developmental delay.2011] [Fragile X syndrome with FMR1 and FMR2 deletion.1999] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion.2011] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]1/1/2016
4
4
Decreased from 4 to 4
Description
There is a well established role for AFF2 (aka FMR2) in FRAXE, an X-linked ID with variable presentation (reviewed in PMID 11246464), but it is unclear whether rates of autism are increased relative to a TD population (see PMIDs 9034011, 21739600, and 22065534 for case reports of FRAXE cases with autism).
Reports Added
[Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.2012] [Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder.2012] [Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.2012] [Using whole-exome sequencing to identify inherited causes of autism.2013] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Autism spectrum disorder: FRAXE mutation, a rare etiology.2014] [Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.2013] [Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressing FRAXE.1997] [Microdeletion of Xq28 involving the AFF2 (FMR2) gene in two unrelated males with developmental delay.2011] [Fragile X syndrome with FMR1 and FMR2 deletion.1999] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion.2011] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015]1/1/2015
4
4
Decreased from 4 to 4
Description
There is a well established role for AFF2 (aka FMR2) in FRAXE, an X-linked ID with variable presentation (reviewed in PMID 11246464), but it is unclear whether rates of autism are increased relative to a TD population (see PMIDs 9034011, 21739600, and 22065534 for case reports of FRAXE cases with autism).
7/1/2014
No data
4
Increased from No data to 4
Description
There is a well established role for AFF2 (aka FMR2) in FRAXE, an X-linked ID with variable presentation (reviewed in PMID 11246464), but it is unclear whether rates of autism are increased relative to a TD population (see PMIDs 9034011, 21739600, and 22065534 for case reports of FRAXE cases with autism).
Reports Added
[Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressing FRAXE.1997] [Fragile X syndrome with FMR1 and FMR2 deletion.1999] [Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion.2011] [Microdeletion of Xq28 involving the AFF2 (FMR2) gene in two unrelated males with developmental delay.2011] [Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.2012] [Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder.2012] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.2012] [Using whole-exome sequencing to identify inherited causes of autism.2013] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Autism spectrum disorder: FRAXE mutation, a rare etiology.2014]4/1/2014
No data
4
Increased from No data to 4
Description
There is a well established role for AFF2 (aka FMR2) in FRAXE, an X-linked ID with variable presentation (reviewed in PMID 11246464), but it is unclear whether rates of autism are increased relative to a TD population (see PMIDs 9034011, 21739600, and 22065534 for case reports of FRAXE cases with autism).
Krishnan Probability Score
Score 0.76554049895673
Ranking 13/25841 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.
ExAC Score
Score 0.99876060447234
Ranking 1121/18225 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
Sanders TADA Score
Score 0.93468579932171
Ranking 12644/18665 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).
Larsen Cumulative Evidence Score
Score 47
Ranking 35/461 scored genes
[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.
Zhang D Score
Score 0.37329434178393
Ranking 1751/20870 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.
External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| Grasp | GRP1 (general receptor for phosphoinositides 1)-associated scaffold protein | Rat | Protein Binding | 192254 | Q8R4T5 |
| Siah1a | E3 ubiquitin-protein ligase SIAH1A | Mouse | Protein Binding | 20437 | P61092 |