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Integrated omics analyses clarifies ATRX copy number variant of uncertain significance

Journal of Human Genetics volume 69, pages 101–105 (2024)Cite this article

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Abstract

Partial duplications of genes can be challenging to detect and interpret and, therefore, likely represent an underreported cause of human disease. X-linked dominant variants in ATRX are associated with Alpha-thalassemia/impaired intellectual development syndrome, X-linked (ATR-X syndrome), a clinically heterogeneous disease generally presenting with intellectual disability, hypotonia, characteristic facies, genital anomalies, and alpha-thalassemia. We describe an affected male with a de novo hemizygous intragenic duplication of ~43.6 kb in ATRX, detected by research genome sequencing following non-diagnostic clinical testing. RNA sequencing and DNA methylation episignature analyses were central in variant interpretation, and this duplication was subsequently interpreted as disease-causing. This represents the smallest reported tandem duplication within ATRX associated with disease. This case demonstrates the diagnostic utility of integrating multiple omics technologies, which can ultimately lead to a definitive diagnosis for rare disease patients.

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Data availability

Care4Rare Canada deposits multi-omic data in a national platform, Genomics4RD (genomics4rd.ca), to facilitate data sharing. Phenotypic and DNA/RNA sequencing data from this family is made available through a controlled access request to Genomics4RD (genomics4rd@cheo.on.ca). There are restrictions to the availability of methylation data in this project due to consent limitations; they may be available from the corresponding author on request.

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Acknowledgements

We thank the family for their participation. We would also like to thank the clinical laboratory, GeneDx, for their support of this research and for providing the ES data. This study was performed under the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI‐147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, and Children’s Hospital of Eastern Ontario Foundation. Episignature analysis through the EpiSign-CAN study was funded by the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188). We would like to acknowledge Wendy Mears for her technical assistance. AEM was supported by a Canadian Institutes of Health Research (CIHR) fellowship award (MFE-176616). KMB was supported by a CIHR Foundation Grant (FDN‐154279) and a Tier 1 Canada Research Chair in Rare Disease Precision Health.

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Authors and Affiliations

  1. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, K1H 5B2, Canada

    Aren E. Marshall, David A. Dyment, Kym M. Boycott, David A. Dyment & Kristin D. Kernohan

  2. Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada

    Yijing Liang & Madeline Couse

  3. Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada

    Haley McConkey & Bekim Sadikovic

  4. Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada

    Haley McConkey & Bekim Sadikovic

  5. Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, K1H 8L1, Canada

    Kym M. Boycott & David A. Dyment

  6. Newborn Screening Ontario, Ontario, ON, K1H 8L1, Canada

    Kristin D. Kernohan

  7. University of Toronto, Toronto, ON, Canada

    Michael Brudno, Christian Marshall, Roberto Mendoza, James Dowling & Robin Hayeems

  8. University of Calgary, Calgary, AB, Canada

    Francois Bernier, Micheil Innes, Ryan Lamont, Jillian Parboosingh, Deborah Marshall & Anna Lehman

  9. University of British Columbia, Vancouver, BC, Canada

    Clara van Karnebeek & Sara Mostafavi

  10. McGill University, Montreal, QC, Canada

    Bartha Knoppers

Authors
  1. Aren E. Marshall
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  2. Yijing Liang
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  3. Madeline Couse
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  4. Haley McConkey
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  5. Bekim Sadikovic
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  6. Kym M. Boycott
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  7. David A. Dyment
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  8. Kristin D. Kernohan
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Consortia

Care4Rare Canada Consortium

  • Kym M. Boycott
  • , Michael Brudno
  • , Francois Bernier
  • , Clara van Karnebeek
  • , David A. Dyment
  • , Kristin D. Kernohan
  • , Micheil Innes
  • , Ryan Lamont
  • , Jillian Parboosingh
  • , Deborah Marshall
  • , Christian Marshall
  • , Roberto Mendoza
  • , James Dowling
  • , Robin Hayeems
  • , Bartha Knoppers
  • , Anna Lehman
  •  & Sara Mostafavi

Corresponding authors

Correspondence to David A. Dyment or Kristin D. Kernohan.

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Competing interests

BS is a shareholder in EpiSign Inc., a biotech company involved in commercialization of EpiSignTM technology.

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Marshall, A.E., Liang, Y., Couse, M. et al. Integrated omics analyses clarifies ATRX copy number variant of uncertain significance. J Hum Genet 69, 101–105 (2024). https://doi.org/10.1038/s10038-023-01203-8

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