RNAseq Supports the Molecular Genetic Diagnosis of Late-Onset ADA Deficiency

  • Christopher M. Watson
  • Claire Stockdale
  • Ian Berry
  • Laura A. Crinnion
  • Ian M. Carr
  • Andrew Cant
  • David T. Bonthron
  • Sinisa SavicEmail author
Letter to Editor

To the Editor:

Adenosine deaminase (ADA) deficiency is an autosomal recessive disorder of purine metabolism that typically presents as a severe combined immunodeficiency in infancy (OMIM: 102700). Approximately 10–15% of patients have a delayed clinical onset (6–24 months) and a smaller proportion present later still (4 years to adulthood) with a milder phenotype and gradual immunological deterioration [1].

Despite the expanding application of modern genetic techniques, the diagnosis of primary immunodeficiencies (PIDs) can be difficult due to the ever-increasing phenotypic heterogeneity of these disorders [2]. Here, we report a case of late-onset ADA deficiency caused by two novel mutations. Both the clinical and genetic diagnoses were challenging and only achieved following the application of several molecular approaches. This case also illustrates the increasing importance of collaborative working between clinicians and laboratory diagnostic scientists.

A 7-year-old girl was...


Funding Sources

This work is supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre and a Medical Research Council grant awarded to Professor Bonthron (MR/M009084/1).

Compliance with Ethical Standards

Disclosure of Potential Conflict of Interest

The authors declare that they have no conflicts of interest.


The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Supplementary material

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  1. 1.
    Flinn AM, Gennery AR. Adenosine deaminase deficiency: a review. Orphanet J Rare Dis. 2018;13:65.CrossRefGoogle Scholar
  2. 2.
    Rae W, Ward D, Mattocks C, Pengelly RJ, Eren E, Patel SV, et al. Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics. Clin Genet. 2018;93:647–55.CrossRefGoogle Scholar
  3. 3.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Exome aggregation consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.CrossRefGoogle Scholar
  4. 4.
    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefGoogle Scholar
  5. 5.
    Hershfield MS. Genotype is an important determinant of phenotype in adenosine deaminase deficiency. Curr Opin Immunol. 2013;15:571–7.CrossRefGoogle Scholar
  6. 6.
    Ameur A, Kloosterman WP, Hestand MS. Single-molecule sequencing: towards clinical applications. Trends Biotechnol. 2018;S0167-7799:30204.Google Scholar
  7. 7.
    Department of Health and Social Care. Matt Hancock announces ambition to map 5 million genomes. Last accessed: 29th October 2018.
  8. 8.
    Ellingford JM, Beaman G, Webb K, O’Callaghan C, Hirst RA, on behalf of the 100,000 Genomes Project, Black GCM, Newman WG. Whole genome sequencing enables definitive diagnosis of Cystic Fibrosis and Primary Ciliary Dyskinesia. bioRxiv 2018;438838.
  9. 9.
    Cummings BB, Marshall JL, Tukiainen T, Lek M, Donkervoort S, Foley AR, et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med. 2017;9:386.CrossRefGoogle Scholar
  10. 10.
    Ameur A, Kloosterman WP, Hestand MS. Single-molecule sequencing: towards clinical applications. Trends Biotechnol. 2018;S0167-7799:30204.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Yorkshire Regional Genetics Service, The Leeds Teaching Hospitals NHS TrustSt. James’s University HospitalLeedsUK
  2. 2.Leeds Institute of Medical Research, University of LeedsSt. James’s University HospitalLeedsUK
  3. 3.Department of Clinical Immunology and AllergySt. James’s University HospitalLeedsUK
  4. 4.Northern Institute for Cancer Research, Tyne; and the Institute of Cellular MedicineNewcastle University Medical SchoolNewcastle upon TyneUK
  5. 5.National Institute for Health Research, Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), Wellcome Trust Brenner BuildingSt. James’s University HospitalLeedsUK

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