Investigating the genetic susceptibility to exertional heat illness.
J Med Genet
; 57(8): 531-541, 2020 08.
Article
en En
| MEDLINE
| ID: mdl-32054689
ABSTRACT
BACKGROUND:
We aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap.METHODS:
The coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature.RESULTS:
We found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI.CONCLUSION:
We confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Rabdomiólisis
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Trastornos de Estrés por Calor
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Canal Liberador de Calcio Receptor de Rianodina
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Canales de Calcio Tipo L
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
J Med Genet
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido