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Alpha Thalassemia X-linked Intellectual Disability Syndrome

Alpha thalassemia X-linked intellectual disability syndrome, also known as ATR-X syndrome, is a very rare genetic disorder affecting multiple parts of the body. ATR-X syndrome can cause intellectual disability, characteristic facial features, seizures, abnormalities of the genitourinary tract, gastroesophageal reflux and other disorders of the GI system, movement difficulties, and alpha thalassemia. Alpha thalassemia is a blood condition where there is a defect in hemoglobin (the oxygen-carrying component of red blood cells). Despite the name of this condition, alpha thalassemia is not present in every patient with ATR-X syndrome1.

ATR-X syndrome is caused by germline mutations (meaning they are present from the beginning of development and are in all cells of the body) in the ATRX gene on the X chromosome. The ATRX gene is important in regulating the expression of many other genes in various ways, so the effects of having a genetic defect in ATRX are broad (hence the many possible disease features!). The severity of disease that someone with ATR-X syndrome experiences depends on how harmful (pathogenic) their specific gene mutation is, and how much ATRX function is retained2. In fact, as genetic testing is becoming more widely accessible, more patients are being diagnosed with ATR-X syndrome who have significantly milder disease than the classic descriptions2. ATR-X syndrome mostly affects males (see below).

 

Females with ATR-X Syndrome

Female carriers of ATR-X syndrome, i.e. females with an ATRX gene variant on one of their X chromosomes (heterozygotes), are usually asymptomatic without any symptoms of disease. This is because most female carriers of the condition develop significant skewing of their X chromosome inactivation that favors the normal X chromosome (the X chromosome with the correct copy of the ATRX gene)3. For a more detailed description, see below:

X-inactivation occurs in all cells of a female fetus early in development, where each cell inactivates one of their two X chromosomes, leaving only one active. Because this is a random process, this usually results in even (~50:50) expression of each X chromosome across the cells in the body. In female carriers of ATRX, the early cells that inactivate the normal X chromosome are left with no functioning ATRX gene, so they are less likely to survive compared to the cells that inactivated the mutant X chromosome (and thus still have an active normal copy of the ATRX gene). Because of this, as their cells continue to develop and multiply, females end up with skewage of their X chromosome expression favoring the normal copy (90:10 of normal:mutated)3,4. This protects female carriers from the effects of the disease, as a vast majority of their cells have normal ATRX gene expression. This process is consistently present among female carriers of ATR-X syndrome and in fact, testing for the skewage pattern can be used to detect carriers of the disease. Seventy to eighty percent of mothers of males with ATR-X syndrome are carriers of the disease (the remaining males have the disease because of de novo [new] mutations)2.

Of note, asymptomatic female carriers of ATR-X syndrome often still have some hemoglobin H inclusions (a type of hemoglobin that forms when someone has alpha thalassemia) in their blood, which simply indicates that some cells in body do not have a functioning ATRX gene. These inclusions, at the levels they are seen, should not cause clinical problems or require treatment.

There are occasional exceptions to the protective X-inactivation process, with some rare females reported to have symptoms of ATR-X syndrome. One study reported a female whose X inactivation was not skewed and remained balanced (~50:50), and she had notable intellectual disability4. Thus, having 50% of cells in the body express the normal ATRX gene is likely not enough to compensate for the defect in the other half. Another study reported a family in which 3 females showed signs of ATR-X syndrome, suggesting that in rare families, the protective X-inactivation skewing may be less effective. Another symptomatic female–with intellectual impairment, poor growth, and abnormal facial features–was found to have an X-inactivation pattern that was skewed in the other direction, favoring expression of the mutated X chromosome rather than the normal X5. This was a rare case and the cause remains unknown.

This page was last updated in July, 2026. Please note that research into females with this condition is limited and the number of reported cases is small. Decisions regarding your own health should be made in consultation with your medical provider.

  1. Alpha Thalassemia X-linked Intellectual Disability Syndrome – Symptoms, Causes, Treatment | NORD. Accessed July 22, 2026. https://rarediseases.org/rare-diseases/alpha-thalassemia-x-linked-intellectual-disability-syndrome/ 
  2. León NY, Harley VR. ATR-X syndrome: genetics, clinical spectrum, and management. Hum Genet. 2021;140(12):1625-1634. doi:10.1007/s00439-021-02361-5 
  3. Gibbons RJ, Suthers GK, Wilkie AO, Buckle VJ, Higgs DR. X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis. Am J Hum Genet. 1992;51(5):1136-1149. Accessed July 22, 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC1682840/ 
  4. Wada T, Sugie H, Fukushima Y, Saitoh S. Non-skewed X-inactivation may cause mental retardation in a female carrier of X-linked α-thalassemia/mental retardation syndrome (ATR-X): X-inactivation study of nine female carriers of ATR-X. Am J Med Genet A. 2005;138A(1):18-20. doi:10.1002/ajmg.a.30901 
  5. Badens C, Martini N, Courrier S, et al. ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern. Am J Med Genet A. 2006;140A(20):2212-2215. doi:10.1002/ajmg.a.31400