ATRXalpha thalassemia/mental retardation syndrome X-linked
Autism Reports / Total Reports
9 / 23Rare Variants / Common Variants
36 / 0Aliases
ATRX, RP5-875J14.1, ATR2, JMS, MGC2094, MRXHF1, RAD54, RAD54L, SFM1, SHS, XH2, XNP, ZNF-HXAssociated Syndromes
-Genetic Category
Rare Single Gene Mutation, SyndromicChromosome Band
Xq21.1Associated Disorders
EPS, ASDRelevance 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
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
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.
4/1/2020

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

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

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.
Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]7/1/2018

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

Increased from 4 to 5.4 + acc2
Description
4
10/1/2017

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

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

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

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]1/1/2016

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]7/1/2015

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

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
[Large-scale discovery of novel genetic causes of developmental disorders.2014] [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]7/1/2014

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

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]
ExAC Score
Score 0.99999998229899
Ranking 151/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.94867191235614
Ranking 17779/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 3
Ranking 330/461 scored genes
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Zhang D Score
Score 0.44287572195433
Ranking 989/20870 scored genes
[Show Scoring Methodology]
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 |
---|---|---|---|---|---|
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 |