# Whole exome sequencing may be insufficient to cover the causality spectrum of rhabdomyolysis

Josef Finsterer, Sinda Zarrouk-Mahjoub

► To cite this version:

Josef Finsterer, Sinda Zarrouk-Mahjoub. Whole exome sequencing may be insufficient to cover the causality spectrum of rhabdomyolysis. Molecular Genetics and Metabolism Reports, 2018, 17, pp.18. 10.1016/j.ymgmr.2018.08.001. pasteur-02003296

HAL Id: pasteur-02003296

https://riip.hal.science/pasteur-02003296

Submitted on 1 Feb 2019

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Correspondence

Whole exome sequencing may be insufficient to cover the causality spectrum of rhabdomyolysis

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ARTICLE INFO

Keywords:

Mitochondrial

mtDNA

Phenotype

Genotype

Rhabdomyolysis

Whole exome sequencing

Pathogenicity

We read with interest the article by Sambuughin et al. about a ge-
netic study of seven adult males with recurrent exercise-induced
rhabdomyolysis [1]. The study raised the following comments.

We do not agree with the notion that rhabdomyolysis generally
manifests with myalgia [1]. On the contrary, rhabdomyolysis is fre-
quently a painless condition, manifesting with fatigue, exercise intol-
erance, and myoglobinuria. Too match, patient R465 did not complain
about myalgia but about chest pain [1].

Additionally, the authors mix up electromyography with nerve-
conduction studies. In patient R302 no sensory nerve action potential of
the right peroneal nerve could be elicited [1], being interpreted as
mononeuropathy of this nerve. Nerve-conduction studies were normal
in the other six patients. Were nerves other than the peroneal nerve
stimulated in patient R302? Which were the findings on needle elec-
tromyography in the seven patients?

Another shortcoming of the study is that mtDNA was obviously not
covered by WES. Thus, mutations in mtDNA located genes going along
with rhabdomyolysis may have been missed.

Furthermore, it is unclear which criteria were applied to assess a
mutation as “pathogenic”, “likely pathogenic”, “VUS”, or “likely be-
nign”. Were all variants detected by WES confirmed by Sanger se-
quencing? For assessing if a variant is pathogenic, segregation of the
variant with the phenotype through generations needs to be docu-
mented [2]. Were variants or phenotypic features of the seven patients
also found in their first-degree relatives? No functional data were
provided to assess the effect of a variant on biological functions.

Metabolic myopathies frequently manifest as a multiorgan disease
[3]. Were organs other than the muscle prospectively investigated for
involvement in the underlying genetic defect?

Were any abnormalities of the acyl-carnitine profile detected in any
of the seven patients in addition to patient R469?

Overall, this interesting study could be more meaningful if the

above-mentioned issues would be sufficiently addressed.

Conflict of interest

There are no conflicts of interest.

Funding

No funding was received.

Author contribution

JF: design, literature search, discussion, first draft, SZ-M: literature search, discussion, critical comments.

References

[1] N. Sambuughin, O. Mungunsukh, M. Ren, J.F. Capacchione, I. Horkayne-Szakaly, K. Chuang, S.M. Muldoon, J.K. Smith, F.G. O'Connor, P.A. Deuster, Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in re-current exertional rhabdomyolysis, Mol. Genet. Metab. Rep. 16 (2018) 76-81.

[2] L. Dudakova, V. Stranecky, O. Ulmanova, E. Hlavova, M. Trková, A.L. Vincent, P. Liskova, Segregation of a novel p.(Ser270Tyr) MAF mutation and p.(Tyr56*) CRYGD variant in a family with dominantly inherited congenital cataracts, Mol. Biol. Rep. 44 (2017) 435-440.

[3] J. Finsterer, J. Huber, Multisystem disease, including eosinophilia and progressive hyper-creatine-kinase-emia over 10 years, suggests mitochondrial disorder, Case Rep. Neurol. 9 (2017) 69-75.

Josef Finstererᵃ,*,<fnref n="1" />, Sinda Zarrouk-Mahjoubᵇ,<fnref n="1" />

ᵃ Krankenanstalt Rudolfstiftung, Vienna, Austria

ᵇ University of Tunis El Manar and Genomics Platform, Pasteur Institute of Tunis, Tunisia

E-mail address: fifigs1@yahoo.de (J. Finsterer)

<footnote>* Corresponding author at: Postfach 20, 1180 Vienna, Austria.</footnote>

<footnote n="1">¹ Both authors contributed equally.</footnote>