Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis

Abstract

Exertional rhabdomyolysis is a metabolic event characterized by the release of muscle content into the circulation due to exercise-driven breakdown of skeletal muscle. Recurrent exertional rhabdomyolysis has been associated with metabolic myopathies and mitochondrial disorders, a clinically and genetically heterogeneous group of predominantly autosomal recessive, monogenic conditions. Although genetics factors are well recognized in recurrent rhabdomyolysis, the underlying causes and mechanisms of exercise-driven muscle breakdown remain unknown in a substantial number of cases. We present clinical and genetic study results from seven adult male subjects with recurrent exertional rhabdomyolysis. In all subject, whole exome sequencing identified multiple heterozygous variants in genes associated with monogenic metabolic and/or mitochondrial disorders. These variants consisted of known pathogenic and/or new likely pathogenic variants in combination with other rare deleterious alleles. The presence of heterozygous pathogenic and rare deleterious variants in multiple genes suggests an oligogenic inheritance for exertional rhabdomyolysis etiology. Our data imply that exertional rhabdomyolysis can reflect cumulative effects or synergistic interactions of deleterious variants in multiple genes that are likely to compromise muscle metabolism under the stress of exercise.

Investigating the genetic susceptibility to exertional heat illness

“…However, we found no RYR1 variants in 5 patients with ER with the 11 RYR1 variants found in 9 patients with EHI. We note that Sambuughin et al only found one RYR1 variant in seven patients with ER investigated by whole exome sequencing 38. Of the RYR1 variants found in patients with EHI, p.I3253T (found in patient #10) has been previously reported in combination with a nonsense RYR1 variant in trans in a patient with a congenital core myopathy39 and in a case of EHI from the French military 17.…”

“…The only variant we found in CACNA1S , p.R498H (annotated pathogenic by GAVIN), has not been reported in association with MH and was found in patient #52 with EHI who had a normal IVCT response. Interestingly, Sambuughin et al reported a variant affecting the same amino acid position ( CACNA1S p.R498L) in an individual with a history of EHI 38. CACNA1S , p.R498H and p.R498L have a combined MAF in low-risk populations of 0.00016 suggesting that the discovery of two variants at this amino acid position in a total of 71 patients with EHI/ER is unlikely to be due to chance.…”

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

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

“…On the contrary, rhabdomyolysis is frequently a painless condition, manifesting with fatigue, exercise intolerance, and myoglobinuria.Too match, patient R465 did not complain about myalgia but about chest pain [1]. …”

“…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.…”