Dorota Fiszer

Marie-Anne Shaw

Nickla Fisher

Phil Hopkins

Rachel Robinson

Ruth Charlton

Sarah Hobson

Sarah Shepherd

BMC Anesthesiology

English

PubMed

Crossref

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

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ORAL PRESENTATION 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, Phil Hopkins1,2
From 33rd Annual Meeting of the European Malignant Hyperthermia Group (EMHG)
Wurzburg, Germany. 15-17 May 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 genera-
tion sequencing.
Approval required submission of a gene dossier to the
UK Genetic Testing Network. This document included:
1. An overview of MH and the evidence for involve-
ment of RYR1 and CACNA1S;
2. Details of the genes
3. Current diagnostic approaches
4. Proposed sequencing strategy
5. Gene coverage with proposed strategy
6. Validation strategy
7. Genetic epidemiology of MH
8. Test characteristics (sensitivity, specificity, PPV,
NPV)
9. Cost benefit of new test
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 con-
firmed 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 Clini-
cal Genetic Laboratory Specialists (VKGL). Variants will
be classified using a 5 class system:
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’ details
1Leeds Institute of Biomedical & Clinical Sciences, School of Medicine,
University of Leeds, Leeds, LS9 7TF, UK. 2Malignant Hyperthermia
Investigation Unit, St James’s University Hospital, Leeds, LS9 7TF, UK.
Published: 18 August 2014
doi:10.1186/1471-2253-14-S1-A14
Cite this article as: Fiszer et al.: The introduction of a targeted next
generation sequencing diagnostic service for MH. BMC Anesthesiology
2014 14(Suppl 1):A14.
1Leeds Institute of Biomedical & Clinical Sciences, School of Medicine,
University of Leeds, Leeds, LS9 7TF, UK
Full list of author information is available at the end of the article
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
Fiszer et al. BMC Anesthesiology 2014, 14(Suppl 1):A14
http://www.biomedcentral.com/1471-2253/14/S1/A14
© 2014 Fiszer et al; licensee 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.


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

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

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