Whole-exome sequencing in patients with protein aggregate myopathies reveals causative mutations associated with novel a
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ORIGINAL ARTICLE
Whole-exome sequencing in patients with protein aggregate myopathies reveals causative mutations associated with novel atypical phenotypes Marcin M. Machnicki 1 & Valeria Guglielmi 2 & Elia Pancheri 2 & Francesca Gualandi 3 & Lorenzo Verriello 4 & Katarzyna Pruszczyk 1 & Joanna Kosinska 5 & Antonella Sangalli 6 & Malgorzata Rydzanicz 5 & Maria Grazia Romanelli 6 & Marcella Neri 3 & Rafal Ploski 5 & Paola Tonin 2 & Giuliano Tomelleri 2 & Tomasz Stoklosa 1 & Gaetano Vattemi 2 Received: 4 May 2020 / Accepted: 1 November 2020 # The Author(s) 2020
Abstract 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. Keywords Protein aggregate myopathies . Myofibrillar myopathies . Whole-exome sequencing . LMNA . RYR1 . TTN
Marcin M. Machnicki and Valeria Guglielmi contributed equally to this work. Tomasz Stoklosa and Gaetano Vattemi are Joint last authors * Tomasz Stoklosa [email protected] * Gaetano Vattemi [email protected] 1
Department of Immunology, Medical University of Warsaw, Warsaw, Poland
2
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Verona, Italy
3
UOL of Medical Genetics, Department of Medical Science, University of Ferrara, Ferrara, Italy
4
Neurologic Clinic, Department of Neurological Sciences, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
5
Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
6
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biology and Genetics, University of Verona, Verona, Italy
Neurol Sci
Introduction Myofibrillar myopathies (MFM) are a group of protein aggregate myopathies (PAM) s
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