Human Gene Module / Chromosome X / AFF2

AFF2AF4/FMR2 family, member 2

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
9 / 14
Rare Variants / Common Variants
32 / 1
Aliases
AFF2, FMR2,  FMR2P,  FRAXE,  MRX2,  OX19
Associated Syndromes
Fragile X syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
Xq28
Associated Disorders
ADHD, ID, ASD, EP, EPS
Relevance 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.

Reports related to AFF2 (14 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 Primary Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressing FRAXE. Abrams MT , et al. (1997) Yes ADHD
Rare Variants   (32)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 10424820 Moore SJ , et al. (1999)
- - copy_number_loss Familial Maternal Multi-generational 21739600 Stettner GM , et al. (2011)
- - copy_number_loss Familial Maternal - 22065534 Sahoo T , et al. (2011)
- - copy_number_loss - - - 22065534 Sahoo T , et al. (2011)
c.2539C>G p.Pro847Ala missense_variant Familial - Multiplex 22511880 Chahrour MH , et al. (2012)
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.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.3088A>C p.Ile1030Leu missense_variant De novo - Simplex 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.1962T>C p.(=) synonymous_variant Unknown - Simplex 22773736 Mondal K , et al. (2012)
c.1017C>T p.(=) synonymous_variant Unknown - Simplex 22773736 Mondal K , et al. (2012)
c.1072C>A p.(=) synonymous_variant Unknown - Multiplex 22773736 Mondal K , et al. (2012)
c.1323C>G p.(=) synonymous_variant Unknown - Multiplex 22773736 Mondal K , et al. (2012)
T>C - intron_variant Unknown - Multiplex 22773736 Mondal K , et al. (2012)
A>G - intron_variant Unknown - Multiplex 22773736 Mondal K , et al. (2012)
A>G - intron_variant Unknown - Multiplex 22773736 Mondal K , et al. (2012)
C>T - intron_variant Unknown - Multiplex 22773736 Mondal K , et al. (2012)
T>G - intron_variant Unknown - Multiplex 22773736 Mondal K , et al. (2012)
c.2458C>T p.Arg820Cys missense_variant Familial Maternal Simplex 23020937 Rauch A , et al. (2012)
c.*8999G >C - 3_prime_UTR_variant Unknown - Multiplex 23092983 Nava C , et al. (2012)
c.835C>T p.Gln283Ter stop_gained Unknown - Unknown 23352160 Lim ET , et al. (2013)
c.2780G>A p.Arg927His missense_variant Unknown - Simplex 23352163 Yu TW , et al. (2013)
c.2662G>A p.Val888Ile missense_variant Familial Maternal Multi-generational 23849776 Jiang YH , et al. (2013)
c.-460_-458GCC(6_25) - trinucleotide_repeat_microsatellite_feature Familial Maternal Simplex 25035088 Correia F , et al. (2014)
c.1640G>A p.Gly547Asp missense_variant Familial Maternal Multiplex 26544041 Zhang Y , et al. (2015)
c.[523dupA;524_525insA;c.527_528del] p.[Ala174fs;Ser175fs;Gly176fs] frameshift_variant Familial Maternal Simplex 28263302 C Yuen RK , et al. (2017)
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 9034011 Abrams MT , et al. (1997)
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
4

Minimal Evidence

4

Score Delta: Score remained at 4.4

4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2017
4
icon
4

Score remained at 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).

1/1/2016
4
icon
4

Score remained at 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).

1/1/2015
4
icon
4

Score remained at 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).

4/1/2014
No data
icon
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.
CNVs associated with AFF2(1 CNVs)
Xq28 58 Deletion-Duplication 76  /  415
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
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