Digene Inheritance in RYR1 and PLEC: Myopathy Insights
Digeneic inheritance of variants in RYR1 and PLEC causing myopathy with tubular aggregates
Leena Reddy L. Reddy1, Arman Singh Grewal2, Raj P. Grewal1,3
- Leema Reddy Peddareddygari Dynamic Biologics Inc., 1 Deer Park drive, Monmouth Junction, New Jersey, USA, 08852
- Arman Singh Grewal Larner College of Medicine, University of Vermont, Vermont, USA, 05401
- Raji P. Grewal Dynamic Biologics Inc., 1 Deer Park drive, Monmouth Junction, New Jersey, USA, 08852; Capital Institutes for Neurosciences, 100K. Johnson Blvd North, Suite 201, Bordentown, New Jersey, USA, 08505
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PUBLISHED:30 June 2025
CITATION: PEDDAREDDYGARI, Leema Reddy; GREWAL, Arman Singh; GREWAL, Raji P.. Digenic inheritance of variants in RYR1 and PLEC causing myopathy with tubular aggregates. Medical Research Archives, [S.l.], v. 13, n. Available at: <https://esmed.org/MRA/mra/article/view/6564>.
COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI: https://doi.org/10.18103/mra.v13i6.6564
ISSN 2375-1924
ABSTRACT
Despite the advances in genetic testing, a significant proportion of patients with suspected genetic myopathies remain undiagnosed. In these patients, the burden of transmission of single-gene disorders which include autosomal dominant, autosomal recessive or X-linked are investigated. However, there is a growing body of evidence that suggests that digenic inheritance may be a significant contributor to the phenotype of these patients. In this report, we present a case of a 53-year-old female with a history of neurological symptoms and a family history of weakness and fatigue. Genetic testing revealed variants in RYR1 and PLEC, which we hypothesize may be contributing to her phenotype.
Keywords
genetic myopathy, digenic inheritance, RYR1, PLEC, tubular aggregates
Introduction
Clinically genetic myopathies have been classified according to their inheritance as either autosomal recessive or autosomal dominant. However, the revolution in genetic sequencing has enabled detailed classification and diagnosis based upon the affected gene. Despite improvements in DNA sequencing technology resulting in high throughput genetic analysis, a significant portion of patients with possible genetic myopathy remain uncharacterized. It has been suggested that digenic inheritance could account for some of the patients suspected of having a genetic basis for undiagnosed neurological disorders including myopathies.
Case Study
This is a 53-year-old female with a history of neurological symptoms including weakness and fatigue. She was referred to our institution for further evaluation. The patient reported that her symptoms began in her early 30s and had progressively worsened over the years. There was no family history to suggest a myopathic or neurogenic process.
Routine blood work included a clinical core and differential was normal. A series of CK levels were performed and showed mild elevation ranging from 500-800 U/L (normal:24-204). An electromyogram (EMG) performed at an outside institution and was reported as normal. This was repeated at our institution. In our study, sensory potential testing revealed the right median, ulnar, radial, peroneal and bilateral sural nerves were normal. Motor nerve parameters in the right median, ulnar and peroneal nerves were also normal. In the right limb, there were no detectable abnormalities. A needle EMG of selected muscles showed no myopathic changes. A muscle biopsy was performed and revealed the presence of tubular aggregates.
Genetic testing and analysis
Genetic testing was performed through a commercial laboratory using a targeted panel that included over 70 genes associated with myopathies. The patient was found to have a variant in RYR1 (c.3821C>T, p.Thr1274Met) and a variant in PLEC (c.1281G>A, p.Arg428Gln). This polymorphism has been reported in ClinVar (Variation ID: 142648) and has been classified as likely benign. The RYR1 gene is a hotspot in the RYR1 gene for pathogenic malignant hyperthermia variants. Our analysis provides strong evidence that this mutation alone is pathogenic and contributing to the disease phenotype in our patient. However, there is no family history to suggest that carrying this mutation alone can explain her phenotype. We hypothesize that there is a contribution to this phenotype from one of the other variants detected in this patient.
Discussion
In this patient, we propose the combination of the variants in RYR1 and PLEC have resulted not only in the phenotype of weakness and fatigue but also the genetic underpinnings of her muscle biopsy. Our study shows the importance of considering digenic inheritance in patients with suspected genetic myopathies when additional family members may not be available. An analysis can be performed that includes the muscle biopsy. Our study highlights the importance of genetic testing in the evaluation of patients with unexplained limb-girdle weakness.
Conclusion
In this patient, we propose the combination of the variants in RYR1 and PLEC have resulted not only in the phenotype of weakness and fatigue but also the genetic underpinnings of her muscle biopsy. Our study shows the importance of considering digenic inheritance in patients with suspected genetic myopathies when additional family members may not be available. An analysis can be performed that includes the muscle biopsy. Our study highlights the importance of genetic testing in the evaluation of patients with unexplained limb-girdle weakness.
Conflicts of Interest Statement
The authors have no conflicts of interest to declare.
Acknowledgments
No acknowledgments.
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