ATRXalpha thalassemia/mental retardation syndrome X-linked
Autism Reports / Total Reports
14 / 33Rare Variants / Common Variants
45 / 0Aliases
ATRX, RP5-875J14.1, ATR2, JMS, MGC2094, MRXHF1, RAD54, RAD54L, SFM1, SHS, XH2, XNP, ZNF-HXAssociated Syndromes
-Chromosome Band
Xq21.1Associated Disorders
ASD, EPSGenetic Category
Rare Single Gene Mutation, Syndromic, FunctionalRelevance 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
SFARI Genomic Platforms
Reports related to ATRX (33 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 panel | 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 2 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 | - | Rodin RE et al. (2021) | Yes | - |
23 | Support | - | Mitani T et al. (2021) | No | - |
24 | Support | - | Mahjani B et al. (2021) | Yes | - |
25 | Support | - | Verberne EA et al. (2022) | No | - |
26 | Support | - | López-Garrido MP et al. (2022) | Yes | - |
27 | Support | - | Giovenino C et al. (2023) | No | - |
28 | Support | - | Tillotson R et al. (2023) | No | - |
29 | Support | - | Sanchis-Juan A et al. (2023) | No | ASD, epilepsy/seizures |
30 | Support | - | Sheth F et al. (2023) | Yes | DD, ID |
31 | Support | - | Katherine M Quesnel et al. (2023) | Yes | - |
32 | 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 | - |
33 | 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 (45)
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) | |
- | - | copy_number_loss | Familial | Maternal | Simplex | 36879111 | Giovenino C et al. (2023) | |
c.533T>C | p.Val178Ala | missense_variant | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
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.4921T>C | p.Trp1641Arg | missense_variant | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
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.2388A>C | p.Lys796Asn | missense_variant | Familial | Maternal | Simplex | 34582790 | Mitani T et al. (2021) | |
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.7367_7371del | p.Met2456ArgfsTer40 | frameshift_variant | De novo | - | - | 35253369 | Verberne EA et al. (2022) | |
c.1085C>T | p.Thr362Ile | missense_variant | Familial | Both parents | Simplex | 37543562 | Sheth F et al. (2023) | |
c.4865C>T | p.Ala1622Val | missense_variant | Familial | Maternal | Multiplex | 28708303 | Chrot E , et al. (2017) | |
c.4957-4A>G | - | splice_region_variant | Familial | Maternal | Multiplex | 37541188 | Sanchis-Juan A et al. (2023) | |
c.4862C>T | p.Thr1621Met | missense_variant | Familial | Maternal | Simplex | 35593993 | López-Garrido MP et al. (2022) | |
c.6740A>C | p.His2247Pro | missense_variant | Familial | Maternal | Multi-generational | 26997013 | Bouazzi H , et al. (2016) | |
c.7378dup | p.Tyr2460LeufsTer38 | frameshift_variant | De novo | - | Simplex | 25533962 | Deciphering Developmental Disorders Study (2014) | |
c.1565C>G | p.Ser522Cys | missense_variant | Familial | Maternal | Multiplex | 25533962 | Deciphering Developmental Disorders Study (2014) | |
c.6139C>T | p.Leu2047= | missense_variant | Familial | Maternal | Multi-generational | 25533962 | Deciphering Developmental Disorders Study (2014) | |
ENSG00000085224:ENST00000395603:exon20:c.T5212C:p.F1738L,ENSG00000085224:ENST00000373344:exon21:c.T5 | - | missense_variant | De novo | - | - | 33432195 | Rodin RE et al. (2021) |
Common Variants
No common variants reported.
SFARI Gene score
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.
1/1/2021
Score remained at 1
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.
4/1/2020
Score remained at 1
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]10/1/2017
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.
7/1/2017
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.
4/1/2017
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
[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
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
[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
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
[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
[Show Scoring Methodology]
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 |