ATRX

Chr XXLDXLR

ATRX chromatin remodeler

Also known as: JMS, MRX52, RAD54, RAD54L, XH2, XNP, ZNF-HX

NCBI Gene: 546 ENSG00000085224 UniProt: P46100 OMIM: 300032

The ATRX protein is a chromatin remodeling ATPase/helicase that regulates gene expression and chromosomal segregation through cell cycle-dependent nuclear matrix and chromatin associations. Mutations cause X-linked alpha-thalassemia/intellectual disability syndrome and related conditions characterized by cognitive disabilities, alpha-thalassemia, and distinctive facial features through loss-of-function mechanisms that alter DNA methylation patterns. The condition follows X-linked inheritance with both dominant and recessive patterns reported.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene contains an ATPase/helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. This protein is found to undergo cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis. Mutations in this gene are associated with X-linked syndromes exhibiting cognitive disabilities as well as 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. [provided by RefSeq, Jul 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Alpha-thalassemia myelodysplasia syndrome, somaticMIM #300448

Alpha-thalassemia/impaired intellectual development syndromeMIM #301040

XLD

Intellectual disability-hypotonic facies syndrome, X-linkedMIM #309580

XLR

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · ATR-X-related syndrome · XL · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

369

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.12

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — ATRX

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 8.22

OE 0.06 (0.03–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.10Z-score

OE missense 0.70 (0.66–0.75)

604 obs / 860.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.12)

0≤0.351.4

Missense OE?0.70 (0.66–0.75)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 5 / 88.5Missense obs/exp: 604 / 860.0Syn Z: -0.82

Background carrier burden — how many people carry a rare variant somewhere in ATRX?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 47

1,555 rare PASS variants

Rare truncating (LoF)

1 in 2,800

48 rare PASS variants

Rare synonymous (reference)

1 in 120

738 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATRX. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 66	1 in 2,800
South Asian	~36k	1 in 42	1 in 7,200
Remaining (unassigned)	~31k	1 in 42	1 in 920
European (Finnish)	~27k	1 in 170	≈ 1 in 13,000
Admixed American	~23k	1 in 46	1 in 2,300
African / African American	~21k	1 in 56	1 in 3,000
East Asian	~20k	1 in 46	1 in 710
Ashkenazi Jewish	~13k	1 in 180	none seen
Middle Eastern	~2,758	1 in 52	≈ 1 in 2,200

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 34 of 35 coding exons well covered in gnomAD exomes; exon 8 marginal. Genomes: all 35.? see exons ↓