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Diagnostics
Original research
Long-read sequencing to resolve the parent of origin of a de novo pathogenic UBE3A variant
  1. Christopher Mark Watson1,2,
  2. Lucy Jackson1,
  3. Laura A Crinnion1,2,
  4. David T Bonthron2,3,
  5. Eamonn Sheridan2,3
  1. 1 North East and Yorkshire Genomic Laboratory Hub, Central Lab, St. James's University Hospital, Leeds, UK
  2. 2 Leeds Institute of Medical Research, University of Leeds, St. James's University Hospital, Leeds, UK
  3. 3 Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK
  1. Correspondence to Dr Christopher Mark Watson, Leeds Teaching Hospitals NHS Trust, Leeds, UK; c.m.watson{at}leeds.ac.uk

Abstract

Background

The ever-increasing capacity of short-read sequencing instruments is driving the adoption of whole genome sequencing (WGS) as a universal approach to the diagnosis of rare genetic disorders. However, many challenging genomic regions remain, for which alternative technologies must be deployed in order to address the clinical question satisfactorily.

Methods

Here we report the use of long-read sequencing to resolve ambiguity over a suspected diagnosis of Angelman syndrome.

Results

Despite a normal chromosomal microarray result and methylation studies at the imprinted 15q11q13 locus, the continued clinical suspicion of Angelman Syndrome prompted trio WGS of the proband and his parents. A de novo heterozygous frameshift variant, c.2370_2373del (NM_130838.2) p.(Asp790Glufs*7), in UBE3A was identified. To determine the parental allele on which this variant arose, long-read sequencing of the flanking genomic region was performed. Comparison of the resulting haplotypes allowed us to determine that the pathogenic frameshift variant arose on the maternal allele, confirming a diagnosis of Angelman syndrome in this case.

Conclusion

Long-read nanopore sequencing provides significant clinical utility when assessing the parental origin of de novo variants.

  • Nanopore Sequencing
  • Human Genetics
  • Molecular Diagnostic Techniques

Data availability statement

Data are available upon reasonable request. Not applicable.

https://doi.org/10.1136/jmedgenet-2021-108314

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    Data availability statement

    Data are available upon reasonable request. Not applicable.

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    Footnotes

    • Twitter @ChrisM_Watson

    • Contributors Project concept: CMW, ES. Experimental work: LJ, LAC. Formal analysis: CMW, DTB, ES. Manuscript draft: CMW, DTB, ES. Manuscript review and editing: All authors. Guarantor: CMW

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests Dr CMW has received travel expenses to speak at an Oxford Nanopore Technologies organised conference.

    • 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.