Human Gene Module / Chromosome X / ATRX

ATRXalpha thalassemia/mental retardation syndrome X-linked

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
9 / 23
Rare Variants / Common Variants
36 / 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
ASD, EPS
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.

Reports related to ATRX (23 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 Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) No Stereotypies
17 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing. Aspromonte MC , et al. (2019) Yes -
18 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder. Munnich A , et al. (2019) Yes -
19 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
20 Support Genetic landscape of autism spectrum disorder in Vietnamese children Tran KT et al. (2020) Yes -
21 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
22 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 -
23 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   (36)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss - - - 7697714 Gibbons RJ , et al. (1995)
c.4635C>T p.Thr1545= stop_gained - - - 7697714 Gibbons RJ , et al. (1995)
c.4641G>T p.Glu1530Ter stop_gained - - - 7697714 Gibbons RJ , et al. (1995)
c.3729A>G p.Gln1243= missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.2302A>G p.Lys768Glu missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.2316T>C p.Cys755Arg missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.3058A>G p.Asn1002Ser missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.3583A>T p.Arg1195Trp missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.3967A>G p.Tyr1305Cys missense_variant - - - 7697714 Gibbons RJ , et al. (1995)
c.5282T>C p.Met1761Thr missense_variant - - - 21267006 Jensen LR , et al. (2011)
c.622C>T p.Arg208Cys missense_variant - - Unknown 31130284 Monies D , et al. (2019)
c.-117C>T - stop_gained Familial Maternal Simplex 32277047 Chevarin M et al. (2020)
c.2429C>A p.Thr810Asn missense_variant - - Multiplex 7697714 Gibbons RJ , et al. (1995)
c.109C>T p.Arg37Ter stop_gained Familial Maternal - 31452935 Feliciano P et al. (2019)
c.6280G>A p.Val2094Ile missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.7253A>T p.Tyr2418Phe missense_variant Unknown - - 31209962 Aspromonte MC , et al. (2019)
c.6863G>A p.Arg2288His missense_variant Familial Maternal - 29158550 Popp B , et al. (2017)
c.109C>T p.Arg37Ter stop_gained Familial Maternal Simplex 25167861 Redin C , et al. (2014)
c.6740A>C p.His2247Pro missense_variant Familial Maternal - 31406558 Munnich A , et al. (2019)
c.1423C>T p.His475Tyr missense_variant Familial Maternal - 28554332 Bowling KM , et al. (2017)
T>A - splice_site_variant Familial Maternal Multi-generational 8644709 Villard L , et al. (1996)
c.109C>T p.Arg37Ter stop_gained Familial Maternal Multiplex 25606380 Moncini S , et al. (2015)
c.7156C>T p.Arg2386Ter stop_gained Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
c.4031A>G p.Lys1344Arg missense_variant Familial Maternal Simplex 23352163 Yu TW , et al. (2013)
c.1972C>T p.Arg658Cys missense_variant Familial Maternal Simplex 32193494 Tran KT et al. (2020)
c.4244A>G p.Asn1415Ser missense_variant Familial Maternal - 31209962 Aspromonte MC , et al. (2019)
c.1676C>T p.Ser559Leu missense_variant Familial Maternal Simplex 26539891 Karaca E , et al. (2015)
c.5027G>C p.Gly1676Ala missense_variant Familial Maternal Multiplex 18361425 Gong X , et al. (2008)
c.1825C>G p.Pro609Ala missense_variant Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
c.1013C>G p.Ser338Cys missense_variant Familial Maternal Multiplex 25167861 Redin C , et al. (2014)
c.308T>A p.Val103Glu missense_variant Familial Maternal Multiplex 26539891 Karaca E , et al. (2015)
c.4865C>T p.Ala1622Val missense_variant Familial Maternal Multiplex 28708303 Chrot E , et al. (2017)
c.6740A>C p.His2247Pro missense_variant Familial Maternal Multi-generational 26997013 Bouazzi H , et al. (2016)
c.1565C>G p.Ser522Cys missense_variant Familial Maternal Multiplex 25533962 Deciphering Developmental Disorders Study (2014)
c.7378dup p.Tyr2460LeufsTer38 frameshift_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.6139C>T p.Leu2047= missense_variant Familial Maternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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.

Score Delta: Score remained at 4

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.

4/1/2020
4
icon
4

Score remained at 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.

10/1/2019
4
icon
1

Decreased from 4 to 1

New Scoring Scheme
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.

7/1/2019
4
icon
4

Decreased 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.

7/1/2018
5.4 + acc2
icon
4

Decreased from 5.4 + acc2 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.

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.

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.

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
[Analysis of X chromosome inactivation in autism spectrum disorders.2008] [Using whole-exome sequencing to identify inherited causes of autism.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [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] [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] [Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).1995] [Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without alpha-thalassemia.1996] [Alpha thalassaemia-mental retardation, X linked.2006] [Rosiglitazone REMS restrictions removed.2014] [Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [Novel ATRX gene damaging missense mutation c.6740A>C segregates with profound to severe intellectual deficiency without alpha thalassaemia.2016] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
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.

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.

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.

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)

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.
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
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).
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.
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.
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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