Health & Medical Question

I need a summary of a 4 page article: “Genomic Screening for Malignant Hyperthermia Susceptibility” (which is downloaded in pdf) Typed in Times Roman style with a font size 12, double-spaced on 1 page only.

Clinical Focus Review
Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M., Editor
Genomic Screening for Malignant Hyperthermia
Susceptibility
Leslie G. Biesecker, M.D., Robert T. Dirksen, Ph.D., Thierry Girard, M.D., Philip M. Hopkins, M.D., Sheila Riazi, M.D.,
Henry Rosenberg, M.D., Kathryn Stowell, Ph.D., James Weber, Ph.D.
alignant hyperthermia (MH) is a syndrome of acutely
disordered skeletal muscle excitation–contraction
coupling leading to fever, acidosis, hypercapnia, tachycardia,
hyperkalemia, muscle rigidity, and rhabdomyolysis that can
be triggered by potent inhalation anesthetics and depolarizing neuromuscular blocking agents (e.g., succinylcholine).1
An MH reaction is challenging to manage, requiring rapid
interventions to halt the procedure, discontinue the triggering agents, administer dantrolene, correct dysrhythmias, and
apply other crucial supportive measures.2,3 Even though early
intervention using these measures is effective in aborting
or ameliorating the reaction, the mortality for a malignant
hyperthermia reaction is still 4 to 10%.4,5 Morbidity is more
common, can be severe, and in some cases long lasting (e.g.,
renal failure). MH susceptibility can be a component of some
congenital myopathies but it is most commonly the only
manifestation in an affected individual and it is this latter manifestation we are focused on here. MH is a heritable trait, primarily associated with variants in either the type 1 ryanodine
receptor (RYR1) intracellular calcium channel or the alpha 1S
subunit (CACNA1S) of the voltage-dependent L-type Ca2+
channel. The disorder is heritable, but it is not always inherited: rare cases have been shown to be due to de novo mutation
events. Another gene associated with MH reactions is STAC3,
although all the reported occurrences involve individuals with
biallelic variants who have an apparent myopathy: here we are
focused on individuals who are asymptomatic until exposed
to a triggering agent. A recent report6 suggested that TRPV1
is also associated with MH, but this has not been confirmed.
Estimates of the prevalence of malignant hyperthermia susceptibility vary widely, from 1/200 to 1/3,000,7–9 although
the clinical incidence of MH reactions is much lower—between 1:10,000 and 1:150,000 general anesthetics.10,11 Of
those who have experienced an MHreaction, 50% to greater
than 70% are found to have at least 1 of more than 200 variants in either RYR1 or CACNA1S, indicating that there is
both locus and allelic heterogeneity.1,12
Research into MH susceptibility over the past decades
has provided important insights into the epidemiology,
pathophysiology, clinical management, and genetics of this
disorder. At the same time, it is recognized that the mortality associated with MH has declined little since the widespread adoption of dantrolene. Given the advancement in
scientific understanding and medical management that has
occurred, we pose to the field a simple and direct question:
what would it take to end deaths from MH?
We are posing this rhetorical question to organize our
thinking and direct our clinical and scientific resources
toward an ideal objective. The complete elimination of
morbidity and mortality from MH is likely impossible
since a complete understanding of the biology of this trait,
identification of all at-risk individuals, and changing their
anesthetic management to the degree needed to drive the
mortality to zero is complex.We argue that it is conceivable
that we can come close to eradicating all deaths from MH
susceptibility or to sufficiently reduce the death rate that
the efforts and expenses would be worthwhile. Going forward, MH susceptibility is an attractive target for a genomic
screening effort for a number of reasons.
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M
• The primary disease manifestation is typically dramatic,
severe, and quantifiable.
• Most people have almost zero risk of MH, a few people
have a high risk, and most of the latter group can be
identified.
• There is relatively little stigma associated with a diagnosis of MH susceptibility so presymptomatic diagnosis is
not highly aversive.
• An operating room MH reaction is completely avoidable in
known susceptible individuals by avoiding exposure to the
triggering agents, which involves decontamination of the
anesthetic workstation and use of alternative anesthetics.
• Genetic tools with the potential to identify individuals
with MH susceptibility are increasingly powerful and
costs are falling rapidly.
Michael J. Avram, Ph.D., served as Handling Editor for this article.
Submitted for publication May 19, 2020. Accepted for publication August 11, 2020. Published online first on September 8, 2020. From the Medical Genomics and Metabolic Genetics
Branch, National Human Genome Research Institute, Bethesda, Maryland (L.G.B.); Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New
York (R.T.D.); Department Anesthesiology, University Hospital Basel, University of Basel, Switzerland (T.G.); MH Investigation Unit, University of Leeds, Leeds, United Kingdom (P.M.H.);
Department of Anesthesiology and Pain Medicine, University of Toronto, Ontario, Canada (S.R.); Malignant Hyperthermia Association of the United States, Sherburne, New York (H.R.);
Department of Biochemistry, Massey University, Palmerston North, New Zealand (K.S.); and Prevention Genetics, Marshfield, Wisconsin (J.W.).
Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved. Anesthesiology 2020; 133:1277–82. DOI: 10.1097/ALN.0000000000003547
ANESTHESIOLOGY, V 133 • NO 6
December 2020
Copyright © 2020, the American Society
of Anesthesiologists,
Inc. Unauthorized reproduction of this article is prohibited.
1277
CLINICAL FOCUS REVIEW
Research to Identify All Genetic Loci that Cause or
Contribute to MH Susceptibility
1. Develop a robust and practical physiologic diagnostic
test.
2. Research to identify all genetic loci that cause or contribute to MH susceptibility.
3. Establish the pathogenicity of all variants in genes that
cause or contribute to MH susceptibility.
4. Develop and pilot genomic screening techniques.
5. Consultation services to confirm MH susceptibility diagnoses and educate individuals with MH susceptibility.
6. Healthcare information systems for real-time support
and resources for the management of a MH reaction and
management of at-risk individuals.
Genomic technologies are rapidly advancing, primarily due to chip-based DNA testing platforms13 and next
generation sequencing.14 Whereas Sanger sequencing of
RYR1 and CACNA1S has been, and remains, expensive, next generation sequencing panel tests that include
these genes are now available at costs well below that of
Sanger sequencing. Next generation exome and genome
sequencing are increasingly available in many countries
and becoming an affordable part of research and health
care. These rapid advances and falling costs enable both
research and clinical genomic testing that were inconceivable just a few years ago. They enable rapid identification
of sequence variants in individuals with putative inherited
diseases. However, these variants may number several thousand in each sample and predicting which variant(s) is(are)
implicated in the disease can be challenging. In MH susceptibility where a single missense variant may be all that is
required, once variants in RYR1, CACNA1S, and STAC3
have been excluded, this approach has proved fruitless to
date. So far, relatively few samples from MH-susceptible
individuals have undergone exome or genome sequencing. If a larger number can be sequenced, we will more
likely be able to identify rare recurrent variants or genes
that have an increased burden of rare variants. We propose
that there should be a coordinated program of clinical and
research testing such that every individual with an MH
reaction or positive contracture test is evaluated by next
generation sequencing to increase the chances of identifying the causative variant(s). This should be a mix of
both clinical testing and clinical research testing. Clinical
sequencing of known MH susceptibility–associated genes
is available from a number of laboratories (see the appendix). Deidentified data from all who are sequenced and
found to harbor a pathogenic, or likely pathogenic variant
(determined as per Richards et al. and Harrison et al.15,16),
should be deposited in a public repository, such as ClinVar
or a dedicated MH database so that all can benefit from
this knowledge. Individuals who are not found to have an
unambiguously pathogenic variant should be referred to a
clinical research program to be further evaluated to better
understand the genetic basis of this disease. The pooling
and organization of these cases and data will add immeasurably to efforts to fully catalog genetic variation associated with MH susceptibility.
Escalation to next generation sequencing may also
prove useful in cases where MH susceptibility is apparently
more genetically complex,12,17 especially if combinations of
rare variants are involved. However, if the genetic model
involves combinations of several more common variants,
sample sizes will need to be even larger and single nucleotide polymorphism chip genotyping is likely to be more
cost-effective.
One can readily envision that accomplishing these objectives
is feasible and if accomplished, we could reduce the risks of
MH at each step of the process from operative planning to discharge. For example, if we can reduce the number of susceptible individuals with who are exposed to a triggering agent
by 75% and reduce the mortality rate of an MH reaction by
75%, then deaths from MH would be reduced by more than
90%.This is an exciting and worthy aim, and we outline some
important considerations for the unmet objectives below.
Develop a Robust and Practical Physiologic
Diagnostic Test
Accurate phenotyping is essential in the genetic investigation of any trait. Singly, none of the clinical signs of an MH
reaction is specific, but a nascent reaction can be recognized
by an astute clinician, and the management imperative is to
abort a reaction as soon as it is suspected. It is now rare for
a reaction to reach such a fulminant stage that the diagnosis
is unequivocal. Even when the proband’s diagnosis could be
made on the basis of their clinical reaction, clinical phenotyping for other family members is challenging. Scientific
advances in the genetics of MH have substantially been
founded on the use of the MH susceptibility phenotype
determined using contracture testing. Indeed, the original
identification of the RYR1 and CACNA1S susceptibility loci, and many other large genetic studies of MH have
come from countries where contracture testing of affected
families is quality-controlled and practicable.
While it might be ideal that contracture testing is universally available, there are numerous barriers to this goal that
are beyond the scope of this commentary. Therefore, the
development of a physiologic diagnostic confirmation test
that is analytically robust, but which can use tissue that can
be sampled locally (ideally less invasively) and transported
to the testing center, would greatly improve accessibility to
MH testing. The challenge here is daunting—although we
would be eager to work toward an alternative clinical phenotyping test, there are no existing data to our knowledge
that point to a ready path to such an assay.
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Anesthesiology 2020; 133:1277–82
Biesecker et al.
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Here, we outline some ideas about what an organized program
to substantially reduce deaths from MH ought to comprise:
Malignant Hyperthermia in the Genomic Era
Establish the Pathogenicity of All Variants
in Genes that Cause or Contribute to MH
Susceptibility
Develop and Pilot Genomic Screening Techniques
A future is coming where large numbers of individuals
undergo genome-wide screening that encompasses many
disease and pharmacogenetic susceptibilities: it is essential
to develop evidence to support this approach on a disease-by-disease basis. We propose that a trial of preoperative screening for MH susceptibility would serve as a proof
of principle to test the applicability and utility of extracting MH-associated variants from genomic or exomic data.
Once a suitable set of pathogenic variants is identified,
genomic screening for MH susceptibility could be piloted
on a population of individuals scheduled for elective surgery.The size and power analysis of such a study will require
more accurate estimates of prevalence and the diagnostic
yield of a given set of pathogenic variants.We propose that
this could be fruitful, even without a clear understanding
Biesecker et al.
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Efforts are underway to comprehensively characterize the
pathogenicity of reported variants in RYR1 and CACNA1S
through the ClinGen Variant Curation Expert Panel process (https://www.clinicalgenome.org/affiliation/50038/,
accessed August 25, 2020). This effort is initially focused
on the variants proposed by the European Malignant
Hyperthermia Group (https://www.emhg.org/, accessed
August 25, 2020), with an adaptation of the American
College of Medical Genetics and Genomics variant
pathogenicity standards.15 These standards, which must be
adapted to take into account knowledge of the biology of
RYR1 and malignant hyperthermia susceptibility, comprise
27 criteria including observations of inheritance, case-control studies, functional studies, and in silico predictors, and
conforms to the current international standard for variant
pathogenicity assertions. A major deficit in being able to
assign pathogenic status is the small number of variants that
have been robustly functionally characterized in relevant
model systems. Current testing is robust, but low throughput. A recent revolution in functional genomics heralds
a realistic prospect of overcoming this bottleneck. Prime
editing, an adaptation of CRISPR technology,18 coupled
with strategies for high-throughput functional assays19 have
the potential to support highly robust functional assessments of all variants, even before they are detected in a
human. If these technologies can be adapted to RYR1 and
other genes implicated in MH susceptibility, they have the
potential to provide for high-throughput, low-cost, functional in vitro assays for every potential variant. This task is
not trivial, but it should be feasible. Even achieving a goal of
assessing the pathogenicity of variants that can account for
80% of known cases of MH susceptibility would create a set
of pathogenic variants that could be employed for clinical
research to test the practicality of preoperative screening.
of penetrance of the variants, because one could eliminate
MH reactions if every person with an at-risk genotype
was administered a nontriggering agent. While general
population screening for MH susceptibility will likely not
be practical for some time, an ever-increasing number of
individuals with variants in RYR1 and CACNA1S are
being identified through secondary findings from exome
and genome sequencing.20,21 These individuals provide
opportunities to study and pilot approaches to presymptomatic diagnosis. When MH-susceptible individuals are
identified through preoperative screening or secondary
findings, and there is no personal or family history of
suspected MH, the presence of the variant represents the
only known risk factor for MH susceptibility in the family. Identifying an individual with MH susceptibility is an
opportunity to classify all members within a family, where
the risk of having MH (50% for first-degree relatives) is
orders of magnitude greater than the general population.
Prospective determination of risk of relatives can therefore
be made by testing for the single variant, which is simpler
to perform and interpret than is exome, panel, or even full
gene testing as the laboratory does not need to interpret
other variants.
Consultation Services to Confirm
Diagnoses and Educate Individuals with MH
Susceptibility
A genetic test, even with physiologic confirmation is not
enough: these individuals also need access to a knowledgeable
provider (most likely anesthesiologist, neurologist specializing
in myopathy, or a clinical geneticist) to engage with the affected
individual to analyze the test results, make the clinical–molecular diagnosis, and educate the patient, their family, and care
provider about their disorder. The affected individual is a key
part of the puzzle—it will be critical that they accept and
understand their diagnosis and its implications to maximize the
likelihood that the information is used to their benefit. Support
groups such as Malignant Hyperthermia Association of the
United States (in North America) can be helpful to identify
experts and provide information (see links in the appendix).
There must be support also for care providers unfamiliar with incorporating genomic test information into
anesthetic management decisions. Taking the data from
the advances we propose into account, professional bodies (such as the American Society of Anesthesiologists)
will need to develop policies and practice standards that
are based on the risk stratification of genomic predictive testing. An analogous approach has been adopted in
obstetrics, where the highly complex noninvasive prenatal genomic screening test has been rapidly taken up, with
clear guidelines and risk determinations. Such guidelines
are no guarantee of good care, nor are they a perfect shield
from liability, but they give providers clear guidance and
substantially lessen risks.
Anesthesiology 2020; 133:1277–82
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CLINICAL FOCUS REVIEW
Healthcare Information Systems for Real-time
Support Resources for the Management of a MH
Reaction and Management of At-risk Individuals
In North America, the Malignant Hyperthermia Association
of the United States provides 24/7 hotline support for clinicians managing patients with a known or suspected MH
reaction (similar resources are available in other countries).
These valuable resources should be universally recognized
and readily used, but additional resources for the identification and management of MH should be developed. Artificial
intelligence–driven22 patient monitoring and clinical decision support tools23 within the electronic health record
could be developed to support preoperative decision-making
regarding test results, facilitate real-time early recognition of
an MH event, and other decisions. Finally, information on
MH susceptibility should be readily portable so that patients
can benefit from it no matter where they receive their care.
Conclusions
None of these approaches alone will accomplish our objective. Instead, we recognize that it will be essential that research,
1280
screening, education, and management are integrated into
a functional whole systems–based approach to end deaths
from MH.This proposal is centered on a genomics-centered
approach to MH susceptibility.This is not to say that a major,
disruptive advance in muscle physiologic testing could not
occur that would change this assessment entirely—disruptive advances are by their nature unpredictable. We propose
a model for organizing the necessary genetic and anesthetic
activities needed to build an integrated system that will capture all events, maximize knowledge, and reduce death and
disability from this disease. We propose a flow diagram that
incorporates all of these activities and builds data and expertise into the future (fig. 1).
Population screening for genetic disease is not risk-free.
There will be false-positive and false-negative results. The
risk of false positives would be that individuals would be
offered nontriggering agents unnecessarily. False negatives
could lead to very rare occurrences of MH. There is also a
risk that by reducing the incidence of MH, anesthesiologists
would be become less familiar with the recognition and
management of a reaction.While the United States’ Genetic
Information Nondiscrimination Act should be protective
Anesthesiology 2020; 133:1277–82
Biesecker et al.
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Fig. 1. A model for the future management of malignant hyperthermia susceptibility risk through genomic screening. The blue boxes
represent the current phenotypic ascertainment approach to malignant hyperthermia susceptibility, where neither contracture tests nor DNA
testing is practical, and the purple boxes represent the proposed future approach, supplementing the present approach. “Abnormal testing”
means the presence of a variant that is likely to cause malignant hyperthermia susceptibility. “Not abnormal testing” is the converse of that
result. Boxes with an asterisk indicate steps that contracture testing should be considered to assess malignant hyperthermia risk. Note that
contracture testing may be done before DNA testing or reserved for those who show no abnormality on sequencing. The phrase “history
of malignant hyperthermia” should be considered as at least a reasonably strong history and “malignant hyperthermia reaction” should be
considered as at least reasonably strong evidence of a malignant hyperthermia reaction.
Malignant Hyperthermia in the Genomic Era
in most cases, it is possible that some individuals who are
diagnosed by screening (true or false positive) could be, for
example, denied entry to the Armed Forces.
We recognize that these goals are grand and challenging.
We also recognize, and indeed hope, that others will debate
and help us to refine our proposals and weigh in with different approaches that could help us work toward the goal
of ending deaths from MH.
Research Support
Competing Interests
Dr.Weber is the CEO and part owner of Prevention Genetics
(Marshfield, Wisconsin). Dr. Biesecker reports research support from ArQule (now wholly owned by Merck, Inc.,
Kenilworth, New Jersey), Pfizer, Inc. (New York, New York),
and honoraria from Cold Spring Harbor Laboratory (Cold
Spring Harbor, New York). Dr. Riazi reports research support
from Norgine Pharmaceuticals (Amsterdam, the Netherlands).
The remaining authors declare no competing interests.
Correspondence
Address correspondence to Dr. Rosenberg: President,
Malignant Hyperthermia Association of the United States,
Post Office Box 1069, Sherburne, New York 13460. henryrosenbergmd@gmail.com. Anesthesiology’s articles are made
freely accessible to all readers on www.anesthesiology.org, for
personal use only, 6 months from the cover date of the issue.
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Anesthesiology 2020; 133:1277–82
Copyright © 2020, the American Society of Anesthesiologists, Inc. Unauthorized reproduction of this article is prohibited.
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Appendix: Online Resources
Malignant Hyperthermia Association of the United
States (MHAUS): https://www.mhaus.org. Accessed
August 25, 2020.
The North American Malignant Hyperthermia Registry
of MHAUS: https://anest.ufl.edu/namhr. Accessed August
25, 2020.
European Malignant Hyperthermia Group (EMHG):
https://www.emhg.org. Accessed August 25, 2020.
Genetic Test Registry for RYR1 testing: https://www.ncbi.
nlm.nih.gov/gtr/all/tests/?term=6261%5Bgeneid%5D.
Accessed August 25, 2020.
GeneticTest Registry for CACNA1S testing:https://www.
ncbi.nlm.nih.gov/gtr/all/tests/?term=779%5Bgeneid
%5D. Accessed August 25, 2020.
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Copyright © 2020, the American Society of Anesthesiologists, Inc. Unauthorized reproduction of this article is prohibited.
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