Abstract
Background
Intellectual disability (ID) features in numerous heritable medical conditions that result from ATRX mutations. Alpha-thalassemia mental retardation syndrome (ATR-X syndrome) is the most notable manifestation of ATRX dysfunction. In addition to ID, genitourinary and craniofacial abnormalities are regularly observed with or without alpha-thalassemia.
Aims
The study sought to characterize two cases of ATR-X in a Yemeni family clinically and molecularly.
Methods
PCR amplification and Sanger sequencing were used to study the ATRX gene in a Yemeni family. Also, methylation-sensitive PCR was used to perform X-inactivation studies. CADD, SNAP2 and PolyPhen-2 helped to predict the functional consequences of the variant.
Results
Molecular testing revealed a novel hemizygous missense mutation (c.5666T>G) in the ATRX gene in the two Yemeni brothers. This mutation was found in a heterozygous state in the mother, with the chromosome harboring the mutated allele being under strongly skewed X-inactivation.
Conclusions
The mutated gene is predicted to have a disrupted SNF-2 domain at a conserved residue; p.Leu1889Trp, which is deemed functionally damaging. This report offers, for the first time, full clinical and molecular characterization of a novel ATRX variant in an Arab family.
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Acknowledgments
Authors would like to thank the patient and his family for full cooperation. Thanks also go to Dubai Health Authority and Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences for continuous support.
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The study received no funds, and all authors declare that they have no conflict of interest. All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Additionally, informed consent was obtained from all individual participants included in the study.
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Hamzeh, A.R., Nair, P., Mohamed, M. et al. A novel missense mutation in ATRX uncovered in a Yemeni family leads to alpha-thalassemia/mental retardation syndrome without alpha-thalassemia. Ir J Med Sci 186, 333–337 (2017). https://doi.org/10.1007/s11845-016-1418-6
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DOI: https://doi.org/10.1007/s11845-016-1418-6