Skip to main content

Advertisement

Log in

ATR-X syndrome: genetics, clinical spectrum, and management

  • Review
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

ATR-X, an acronym for alpha thalassemia and mental retardation X-linked, syndrome is a congenital condition predominantly affecting males, characterized by mild to severe intellectual disability, facial, skeletal, urogenital, and hematopoietic anomalies. Less common are heart defects, eye anomalies, renal abnormalities, and gastrointestinal dysfunction. ATR-X syndrome is caused by germline variants in the ATRX gene. Until recently, the diagnosis of the ATR-X syndrome had been guided by the classical clinical manifestations and confirmed by molecular techniques. However, our new systematic analysis shows that the only clinical sign shared by all affected individuals is intellectual disability, with the other manifestations varying even within the same family. More than 190 different germline ATRX mutations in some 200 patients have been analyzed. With improved and more frequent analysis by molecular technologies, more subtle deletions and insertions have been detected recently. Moreover, emerging technologies reveal non-classic phenotypes of ATR-X syndrome as well as the description of a new clinical feature, the development of osteosarcoma which suggests an increased cancer risk in ATR-X syndrome. This review will focus on the different types of inherited ATRX mutations and their relation to clinical features in the ATR-X syndrome. We will provide an update of the frequency of clinical manifestations, the affected organs, and the genotype–phenotype correlations. Finally, we propose a shift in the diagnosis of ATR-X patients, from a clinical diagnosis to a molecular-based approach. This may assist clinicians in patient management, risk assessment and genetic counseling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and material

Not applicable.

Code availability

Not applicable.

References

Download references

Acknowledgments

We thank Dr Alejandra Reyes and Dr Stefan Bagheri-Fam for critical reading of the manuscript. 

Funding

This research was funded by National Health and Medical Research Council Grant 2002426 and Fellowship APP1154870, awarded to VRH. This work was supported by the Monash International Tuition Scholarship and Monash Graduate Scholarship, awarded to NYL. The Hudson Institute is supported by the Operational Infrastructure Scheme of the State Government of Victoria, Australia.

Author information

Authors and Affiliations

Authors

Contributions

Nayla Y. León performed the literature search. Nayla Y. Leon and Vincent R. Harley created the concept, wrote the manuscript, prepared tables, developed the figures and approved the final version.

Corresponding author

Correspondence to Vincent R. Harley.

Ethics declarations

Conflicts of interest/Competing interests

The authors declare no conflict of interest. 

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

León, N.Y., Harley, V.R. ATR-X syndrome: genetics, clinical spectrum, and management. Hum Genet 140, 1625–1634 (2021). https://doi.org/10.1007/s00439-021-02361-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-021-02361-5

Navigation