Human Gene Module / Chromosome X / ATRX

ATRXalpha thalassemia/mental retardation syndrome X-linked

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
5 / 17
Rare Variants / Common Variants
29 / 0
Aliases
ATRX, RP5-875J14.1,  ATR2,  JMS,  MGC2094,  MRXHF1,  RAD54,  RAD54L,  SFM1,  SHS,  XH2,  XNP,  ZNF-HX
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
Xq21.1
Associated Disorders
EPS, ASD
Relevance to Autism

A rare mutation in the ATRX gene has been identified with ASD (Gong et al., 2008).

Molecular Function

The protein encoded by this gene contains an ATPase/helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. Mutations in this gene are associated with an X-linked mental retardation (XLMR) syndrome most often accompanied by alpha-thalassemia (ATRX) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported.

External Links
Gene CardEntrez GeneOMIMUniProtHumanBasePubMed
Reports related to ATRX (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Alpha thalassaemia-mental retardation, X linked. Gibbons R (2006) No Epilepsy, ASD
2 Support Analysis of X chromosome inactivation in autism spectrum disorders. Gong X , et al. (2008) Yes -
3 Support Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1. Jensen LR , et al. (2011) No -
4 Support Using whole-exome sequencing to identify inherited causes of autism. Yu TW , et al. (2013) Yes -
5 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ... Brett M , et al. (2014) Yes MCA
6 Recent Recommendation Rosiglitazone REMS restrictions removed. Traynor K (2014) No -
7 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
8 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) Yes -
9 Support ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing. Moncini S , et al. (2015) No -
10 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Karaca E , et al. (2015) No Microcephaly
11 Support Novel ATRX gene damaging missense mutation c.6740A>C segregates with profound to severe intellectual deficiency without alpha thalassaemia. Bouazzi H , et al. (2016) No Stereotypies, absent speech
12 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No Hypotonia, spasticity
13 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No -
14 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
15 Support Exome Pool-Seq in neurodevelopmental disorders. Popp B , et al. (2017) No Hypotonia
16 Support Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Gibbons RJ , et al. (1995) No -
17 Support Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without alpha-thalassemia. Villard L , et al. (1996) No Autistic behavior
Rare Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.5027G>C p.Gly1676Ala missense_variant Familial Maternal Multiplex 18361425 Gong X , et al. (2008)
c.5282T>C p.Met1761Thr missense_variant - - - 21267006 Jensen LR , et al. (2011)
c.4031A>G p.Lys1344Arg missense_variant Familial Maternal Simplex 23352163 Yu TW , et al. (2013)
c.7156C>T p.Arg2386Ter stop_gained Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
c.1825C>G p.Pro609Ala missense_variant Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
c.109C>T p.Arg37Ter stop_gained Familial Maternal Simplex 25167861 Redin C , et al. (2014)
c.1013C>G p.Ser338Cys missense_variant Familial Maternal Multiplex 25167861 Redin C , et al. (2014)
c.1565C>G p.Ser522Cys missense_variant Familial Maternal Multiplex 25533962 Deciphering Developmental Disorders Study (2014)
c.7378dupT p.Tyr2460LeufsTer38 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.6139C>T p.Arg2047Cys missense_variant Familial Maternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
c.109C>T p.Arg37Ter stop_gained Familial Maternal Multiplex 25606380 Moncini S , et al. (2015)
c.533T>A p.Val178Asp missense_variant Familial Maternal Multiplex 26539891 Karaca E , et al. (2015)
c.1676C>T p.Ser559Leu missense_variant Familial Maternal Simplex 26539891 Karaca E , et al. (2015)
c.6740A>C p.His2247Pro missense_variant Familial Maternal Multi-generational 26997013 Bouazzi H , et al. (2016)
c.1423C>T p.His475Tyr missense_variant Familial Maternal - 28554332 Bowling KM , et al. (2017)
c.4865C>T p.Ala1622Val missense_variant Familial Maternal Multiplex 28708303 Chrot E , et al. (2017)
c.6280G>A p.Val2094Ile missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.6863G>A p.Arg2288His missense_variant Familial Maternal - 29158550 Popp B , et al. (2017)
- - copy_number_loss - - - 7697714 Gibbons RJ , et al. (1995)
c.2302A>G p.His750Arg missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.2316T>C p.Cys755Arg missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.2429G>T p.Lys792Asn missense_variant - - Multiplex 7697714 Gibbons RJ , et al. (1995)
c.3058A>G p.Asn1002Ser missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.3583A>T p.Asp1177Val missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.3729T>C p.Tyr1226His missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.3967A>G p.Tyr1305Cys missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.4635C>T p.Arg1528Ter stop_gained - - - 7697714 Gibbons RJ , et al. (1995)
c.4641G>T p.Glu1530Ter stop_gained - - - 7697714 Gibbons RJ , et al. (1995)
T>A - splice_site_variant Familial Maternal Multi-generational 8644709 Villard L , et al. (1996)
Common Variants  

No common variants reported.

SFARI Gene score
4

Minimal Evidence

4

Score Delta: Increased from 4 to 5.4 + acc2

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2018
4
icon
5.4 + acc2

Increased from 4 to 5.4 + acc2

Description

4

10/1/2017
4
icon
4

Increased from 4 to 4

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425). Maternally-transmitted missense variants in ATRX have been identified in male ASD probands (PMIDs 23352163, 25533962), as well as a female ASD proband with a brother presenting with ADHD (PMID 24690944); however, segregation of these variants in multipex families was not determined.

Reports Added
[Exome Pool-Seq in neurodevelopmental disorders.2017] [Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
7/1/2017
4
icon
4

Increased from 4 to 4

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425). Maternally-transmitted missense variants in ATRX have been identified in male ASD probands (PMIDs 23352163, 25533962), as well as a female ASD proband with a brother presenting with ADHD (PMID 24690944); however, segregation of these variants in multipex families was not determined.

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
4/1/2017
4
icon
4

Increased from 4 to 4

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425). Maternally-transmitted missense variants in ATRX have been identified in male ASD probands (PMIDs 23352163, 25533962), as well as a female ASD proband with a brother presenting with ADHD (PMID 24690944); however, segregation of these variants in multipex families was not determined.

Reports Added
[Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.2011] [Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).1995] [Novel ATRX gene damaging missense mutation c.6740A>C segregates with profound to severe intellectual deficiency without alpha thalassaemia.2016] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Analysis of X chromosome inactivation in autism spectrum disorders.2008] [Rosiglitazone REMS restrictions removed.2014] [Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without alpha-thalassemia.1996] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Using whole-exome sequencing to identify inherited causes of autism.2013] [ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing.2015] [Alpha thalassaemia-mental retardation, X linked.2006]
4/1/2016
4
icon
4

Increased from 4 to 4

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425). Maternally-transmitted missense variants in ATRX have been identified in male ASD probands (PMIDs 23352163, 25533962), as well as a female ASD proband with a brother presenting with ADHD (PMID 24690944); however, segregation of these variants in multipex families was not determined.

Reports Added
[Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [Alpha thalassaemia-mental retardation, X linked.2006] [Novel ATRX gene damaging missense mutation c.6740A>C segregates with profound to severe intellectual deficiency without alpha thalassaemia.2016] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.2011] [ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing.2015] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).1995] [Rosiglitazone REMS restrictions removed.2014] [Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without alpha-thalassemia.1996] [Analysis of X chromosome inactivation in autism spectrum disorders.2008] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Using whole-exome sequencing to identify inherited causes of autism.2013]
1/1/2016
4
icon
4

Increased from 4 to 4

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425). Maternally-transmitted missense variants in ATRX have been identified in male ASD probands (PMIDs 23352163, 25533962), as well as a female ASD proband with a brother presenting with ADHD (PMID 24690944); however, segregation of these variants in multipex families was not determined.

Reports Added
[Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [Alpha thalassaemia-mental retardation, X linked.2006] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Rosiglitazone REMS restrictions removed.2014] [Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.2011] [Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without alpha-thalassemia.1996] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).1995] [ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing.2015] [Analysis of X chromosome inactivation in autism spectrum disorders.2008] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Using whole-exome sequencing to identify inherited causes of autism.2013]
7/1/2015
6
icon
4

Decreased from 6 to 4

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425). Maternally-transmitted missense variants in ATRX have been identified in male ASD probands (PMIDs 23352163, 25533962), as well as a female ASD proband with a brother presenting with ADHD (PMID 24690944); however, segregation of these variants in multipex families was not determined.

1/1/2015
6
icon
6

Decreased from 6 to 6

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425)

Reports Added
[Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing.2015] [Rosiglitazone REMS restrictions removed.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014]
7/1/2014
No data
icon
6

Increased from No data to 6

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425)

4/1/2014
No data
icon
6

Increased from No data to 6

Description

Mutations in this gene are an established cause of an X-linked alpha-thalassemia / ID syndrome, with at least one autistic mutation carrier (PMID 18361425)

Reports Added
[Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014]
Krishnan Probability Score

Score 0.76534961315281

Ranking 24/25841 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 0.99999998229899

Ranking 151/18225 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 0.94867191235614

Ranking 17779/18665 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
Larsen Cumulative Evidence Score

Score 3

Ranking 330/461 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.
Original Source
Zhang D Score

Score 0.44287572195433

Ranking 989/20870 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
CNVs associated with ATRX(1 CNVs)
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Xq21.1 14 Deletion-Duplication 20  /  87
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Daxx Fas death domain-associated protein Mouse Protein Binding 13163 O35613
HIST1H4A histone cluster 1, H4a Human Protein Binding 8359 B2R4R0
MRE11A MRE11 meiotic recombination 11 homolog A (S. cerevisiae) Human Protein Binding 4361 P49959
RAD50 RAD50 homolog (S. cerevisiae) Human Protein Binding 10111 Q92878
WDR1 WD repeat domain 1 Human Protein Binding 9948 O75083
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