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BMC Anesthesiology

Open Access

The introduction of a targeted next generation sequencing diagnostic service for MH

  • Dorota Fiszer1,
  • Sarah Hobson1,
  • Nickla Fisher2,
  • Marie-Anne Shaw1, 2,
  • Sarah Shepherd1,
  • Rachel Robinson1,
  • Ruth Charlton1 and
  • Phil Hopkins1, 2
BMC Anesthesiology201414(Suppl 1):A14

https://doi.org/10.1186/1471-2253-14-S1-A14

Published: 18 August 2014

Background

In this paper we describe how we sought approval and are implementing a diagnostic service for malignant hyperthermia (MH) using clonal targeted next generation sequencing.

Approval required submission of a gene dossier to the UK Genetic Testing Network. This document included:
  1. 1.

    An overview of MH and the evidence for involvement of RYR1 and CACNA1S;

     
  2. 2.

    Details of the genes

     
  3. 3.

    Current diagnostic approaches

     
  4. 4.

    Proposed sequencing strategy

     
  5. 5.

    Gene coverage with proposed strategy

     
  6. 6.

    Validation strategy

     
  7. 7.

    Genetic epidemiology of MH

     
  8. 8.

    Test characteristics (sensitivity, specificity, PPV, NPV)

     
  9. 9.

    Cost benefit of new test

     
  10. 10.

    Referral criteria

     

Following adoption of the dossier by the UGTN and validation of the sequencing strategy in a diagnostic facility, we are now in a position to offer testing. Testing will be offered to families where MH has been confirmed by IVCT and to new index cases. The cost of the sequencing is £530, compared to £3,500 for the IVCT. For index cases, the referring physician will be advised of the pre-test probability for their patient having MH as they may consider IVCT to be more cost-effective when the pre-test probability is low.

Diagnostic reports will be issued in accordance with the joint guideline of the UK Association of Clinical Genetic Science (ACGS) and the Dutch Society of Clinical Genetic Laboratory Specialists (VKGL). Variants will be classified using a 5 class system:
Table 1

5 Class System

Class

Description

Interpretation

1

Clearly not pathogenic

MH not confirmed or excluded

2

Unlikely to be pathogenic

MH not confirmed or excluded

3

Variant of unknown significance (VUS)

MH not confirmed or excluded

4

Likely to be pathogenic

Consistent with diagnosis

5

Clearly pathogenic

Confirms diagnosis

Reports for classes 1 – 3 will advise IVCT.

Variants will be assigned to a class depending on their reported frequency in databases (dbSNP, 1000 Genomes, EVS), segregation analysis and functional analysis.

Authors’ Affiliations

(1)
Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds
(2)
Malignant Hyperthermia Investigation Unit, St James’s University Hospital

Copyright

© Fiszer et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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