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Long-read sequencing for detection and subtyping of Prader-Willi and Angelman syndromes
  1. Vahid Akbari1,2,
  2. Sarah Dada1,3,
  3. Yaoqing Shen1,
  4. Katherine Dixon1,2,
  5. Duha Hejla4,5,
  6. Andrew Galbraith1,3,
  7. Sanaa Choufani6,
  8. Rosanna Weksberg6,7,
  9. Cornelius F Boerkoel2,8,
  10. Laura Stewart4,5,
  11. William T Gibson2,4,
  12. Steven J M Jones1,2,3
  1. 1Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada
  2. 2Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada
  3. 3Bioinformatics Graduate Program, The University of British Columbia, Vancouver, British Columbia, Canada
  4. 4BC Children's Hospital, Vancouver, British Columbia, Canada
  5. 5Division of Endocrinology, Department of Pediatrics, The University of British Columbia, Vancouver, British Columbia, Canada
  6. 6Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  7. 7Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  8. 8BC Women's Hospital, Vancouver, British Columbia, Canada
  1. Correspondence to Dr Steven J M Jones; sjones{at}bcgsc.ca

Abstract

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-q13. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification or methylation-sensitive PCR and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband’s PWS/AS subtype often requires parental samples, a costly process for families and health systems. The use of nanopore sequencing for molecular diagnosis of PWS and AS has been explored by Yamada et al; however, to confirm heterodisomy parental data were still required. Here, we investigate genome-wide nanopore sequencing in a larger cohort of PWS (18) and AS (6) as a singular test to detect the molecular subtype, without parental data. We accurately subtyped these cases including uniparental heterodisomy, mixed iso-/heterodisomy, type 1 and 2 deletions, microdeletion and UBE3A indels. One PWS case with a previously unresolved diagnosis subtyped as maternal isodisomy. This work highlights the application of long-read sequencing and other imprinted regions outside of the PWS/AS critical region to resolve the molecular diagnosis and subtyping of PWS and AS without parental data. The work also outlines an approach to generically detect heterodisomy through the interrogation of distant imprinted regions.

  • DNA Methylation
  • Nanopore Sequencing
  • Genetics, Medical
  • Epigenomics
  • Genomics

Data availability statement

DNA methylation frequency data are available at the Federated Research Data Repository under DOI: 10.20383/103.0962. Other data are not publicly available to retain patient confidentiality; however, data can be obtained from the corresponding author upon reasonable request.

https://doi.org/10.1136/jmg-2024-110115

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    Data availability statement

    DNA methylation frequency data are available at the Federated Research Data Repository under DOI: 10.20383/103.0962. Other data are not publicly available to retain patient confidentiality; however, data can be obtained from the corresponding author upon reasonable request.

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    Footnotes

    • VA and SD contributed equally.

    • Contributors All authors jointly conceived the project. Funding acquisition: SJMJ, WTG, KD, YS, CFB, SC, RW, VA, SD. Patient recruitment and consenting: WTG, DH. Resources: SJMJ, WTG. Supervision: SJMJ, WTG. VA, SD and AG analysed the nanopore data. VA and SD wrote the manuscript. All authors reviewed and edited the manuscript.

    • Funding This work was funded in part through the Canadian Institutes of Health Research grants PJT-168982 and PJT-185999. VA and SD acknowledge funding from the BC Cancer Rising Stars Award. SJMJ acknowledges funding from the Canada Research Chairs programme. Research salary for WTG is supported by an intramural IGAP award from the BC Children’s Hospital Research Institute. RW and SC acknowledge funding from Simons Foundation Autism Research Initiative (SFARI 887172).

    • Competing interests SD, KD and SJMJ have received travel funding from Oxford Nanopore to present at conferences. YS, SC, RW, CFB and SJMJ are affiliated with Alamya Health, which provides genetic sequencing using Oxford Nanopore technology.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.