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Whole-exome sequencing in patients with protein aggregate myopathies reveals causative mutations associated with
Marcin M Machnicki1, Valeria Guglielmi2, Elia Pancheri2
1Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
Background:
Myofibrillar myopathies (MFM) are a subgroup of protein aggregate myopathies (PAM) characterized by a common histological picture of myofibrillar dissolution, Z-disk disintegration, and accumulation of degradation products into inclusions. Mutations in genes encoding components of the Z-disk or Z-disk-associated proteins occur in some patients whereas in most of the cases, the causative gene defect is still unknown. We aimed to search for pathogenic mutations in genes not previously associated with MFM phenotype.
Methods:
We performed whole-exome sequencing in four patients from three unrelated families who were diagnosed with PAM without aberrations in causative genes for MFM.
Results:
In the first patient and her affected daughter, we identified a heterozygous p.(Arg89Cys) missense mutation in LMNA gene which has not been linked with PAM pathology before. In the second patient, a heterozygous p.(Asn4807Phe) mutation in RYR1 not previously described in PAM represents a novel, candidate gene with a possible causative role in the disease. Finally, in the third patient and his symptomatic daughter, we found a previously reported heterozygous p.(Cys30071Arg) mutation in TTN gene that was clinically associated with cardiac involvement.
Conclusions:
Our study identifies a new genetic background in PAM pathology and expands the clinical phenotype of known pathogenic mutations.
Insights
This study identifies novel genetic mutations in LMNA and RYR1 genes linked to protein aggregate myopathies (PAM). It also expands the known clinical effects of TTN gene mutations in affected families.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Myofibrillar myopathies (MFM) are a type of protein aggregate myopathy (PAM) with characteristic myofibrillar and Z-disk abnormalities.
- While some MFM cases are linked to Z-disk gene mutations, the genetic cause remains unknown in most patients.
- This research sought to identify novel causative genes for MFM.
Purpose of the Study:
- To investigate the genetic basis of PAM in patients lacking known MFM gene mutations.
- To identify novel candidate genes associated with the MFM phenotype.
Main Methods:
- Whole-exome sequencing was performed on four patients from three families diagnosed with PAM.
- Genetic analysis focused on identifying mutations in genes not previously associated with MFM.
Main Results:
- A novel heterozygous mutation in LMNA (p.Arg89Cys) was found in one patient and her daughter.
- A potential novel heterozygous mutation in RYR1 (p.Asn4807Phe) was identified in another patient.
- A known heterozygous mutation in TTN (p.Cys30071Arg) with cardiac involvement was found in a third patient and his daughter.
Conclusions:
- This study reveals new genetic factors contributing to PAM.
- The findings broaden the understanding of the clinical spectrum associated with known pathogenic mutations.
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