Whole-exome analyses of congenital muscular dystrophy and congenital myopathy patients from India reveal a wide spectrum of known and novel mutations
Shamita Sanga
National Institute of Biomedical Genomics, Kalyani, India
Contribution: Formal analysis (equal), Investigation (equal), Methodology (equal), Validation (equal), Visualization (equal), Writing - original draft (equal)
Search for more papers by this authorArnab Ghosh
National Institute of Biomedical Genomics, Kalyani, India
Contribution: Formal analysis (supporting), Methodology (equal), Software (equal), Writing - original draft (supporting)
Search for more papers by this authorKrishna Kumar
Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, Kolkata, India
Contribution: Formal analysis (supporting), Investigation (supporting), Methodology (supporting), Writing - original draft (supporting)
Search for more papers by this authorKiran Polavarapu
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (equal), Formal analysis (supporting), Investigation (supporting), Validation (equal)
Search for more papers by this authorVeeramani Preethish-Kumar
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (equal), Resources (equal)
Search for more papers by this authorSeena Vengalil
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorSaraswati Nashi
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorMainak Bardhan
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (equal), Resources (equal)
Search for more papers by this authorGautham Arunachal
Department of Human Genetics, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Validation (supporting), Writing - original draft (supporting)
Search for more papers by this authorSanita Raju
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (equal), Formal analysis (supporting)
Search for more papers by this authorNarayanappa Gayathri
Department of Neuropathology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (supporting), Formal analysis (supporting), Resources (supporting)
Search for more papers by this authorNidhan K. Biswas
National Institute of Biomedical Genomics, Kalyani, India
Contribution: Formal analysis (equal), Methodology (equal), Software (equal), Supervision (equal), Validation (equal), Writing - review & editing (equal)
Search for more papers by this authorSaikat Chakrabarti
Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, Kolkata, India
Contribution: Formal analysis (equal), Investigation (equal), Methodology (equal), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Atchayaram Nalini
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Correspondence
Moulinath Acharya, National Institute of Biomedical Genomics, P.O: N.S.S, Kalyani, West Bengal 741251, India.
Sudipto Roy, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #08-12B, Singapore City 138673, Singapore.
Atchayaram Nalini, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Emails: [email protected] (M. A.); [email protected] (S. R.); [email protected] (A. N.)
Contribution: Conceptualization (equal), Supervision (equal), Validation (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Sudipto Roy
Institute of Molecular and Cell Biology, Singapore City, Singapore
Department of Biological Sciences, National University of Singapore, Singapore City, Singapore
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
Correspondence
Moulinath Acharya, National Institute of Biomedical Genomics, P.O: N.S.S, Kalyani, West Bengal 741251, India.
Sudipto Roy, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #08-12B, Singapore City 138673, Singapore.
Atchayaram Nalini, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Emails: [email protected] (M. A.); [email protected] (S. R.); [email protected] (A. N.)
Contribution: Conceptualization (equal), Funding acquisition (lead), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Moulinath Acharya
National Institute of Biomedical Genomics, Kalyani, India
Correspondence
Moulinath Acharya, National Institute of Biomedical Genomics, P.O: N.S.S, Kalyani, West Bengal 741251, India.
Sudipto Roy, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #08-12B, Singapore City 138673, Singapore.
Atchayaram Nalini, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Emails: [email protected] (M. A.); [email protected] (S. R.); [email protected] (A. N.)
Contribution: Conceptualization (equal), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorShamita Sanga
National Institute of Biomedical Genomics, Kalyani, India
Contribution: Formal analysis (equal), Investigation (equal), Methodology (equal), Validation (equal), Visualization (equal), Writing - original draft (equal)
Search for more papers by this authorArnab Ghosh
National Institute of Biomedical Genomics, Kalyani, India
Contribution: Formal analysis (supporting), Methodology (equal), Software (equal), Writing - original draft (supporting)
Search for more papers by this authorKrishna Kumar
Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, Kolkata, India
Contribution: Formal analysis (supporting), Investigation (supporting), Methodology (supporting), Writing - original draft (supporting)
Search for more papers by this authorKiran Polavarapu
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (equal), Formal analysis (supporting), Investigation (supporting), Validation (equal)
Search for more papers by this authorVeeramani Preethish-Kumar
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (equal), Resources (equal)
Search for more papers by this authorSeena Vengalil
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorSaraswati Nashi
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorMainak Bardhan
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (equal), Resources (equal)
Search for more papers by this authorGautham Arunachal
Department of Human Genetics, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Validation (supporting), Writing - original draft (supporting)
Search for more papers by this authorSanita Raju
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (equal), Formal analysis (supporting)
Search for more papers by this authorNarayanappa Gayathri
Department of Neuropathology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Contribution: Data curation (supporting), Formal analysis (supporting), Resources (supporting)
Search for more papers by this authorNidhan K. Biswas
National Institute of Biomedical Genomics, Kalyani, India
Contribution: Formal analysis (equal), Methodology (equal), Software (equal), Supervision (equal), Validation (equal), Writing - review & editing (equal)
Search for more papers by this authorSaikat Chakrabarti
Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, Kolkata, India
Contribution: Formal analysis (equal), Investigation (equal), Methodology (equal), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Atchayaram Nalini
Department of Neurology, National Institute of Mental Health and Neuroscience, Bengaluru, India
Correspondence
Moulinath Acharya, National Institute of Biomedical Genomics, P.O: N.S.S, Kalyani, West Bengal 741251, India.
Sudipto Roy, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #08-12B, Singapore City 138673, Singapore.
Atchayaram Nalini, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Emails: [email protected] (M. A.); [email protected] (S. R.); [email protected] (A. N.)
Contribution: Conceptualization (equal), Supervision (equal), Validation (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Sudipto Roy
Institute of Molecular and Cell Biology, Singapore City, Singapore
Department of Biological Sciences, National University of Singapore, Singapore City, Singapore
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
Correspondence
Moulinath Acharya, National Institute of Biomedical Genomics, P.O: N.S.S, Kalyani, West Bengal 741251, India.
Sudipto Roy, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #08-12B, Singapore City 138673, Singapore.
Atchayaram Nalini, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Emails: [email protected] (M. A.); [email protected] (S. R.); [email protected] (A. N.)
Contribution: Conceptualization (equal), Funding acquisition (lead), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Moulinath Acharya
National Institute of Biomedical Genomics, Kalyani, India
Correspondence
Moulinath Acharya, National Institute of Biomedical Genomics, P.O: N.S.S, Kalyani, West Bengal 741251, India.
Sudipto Roy, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #08-12B, Singapore City 138673, Singapore.
Atchayaram Nalini, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Emails: [email protected] (M. A.); [email protected] (S. R.); [email protected] (A. N.)
Contribution: Conceptualization (equal), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorAbstract
Background and purpose
Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein-based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods.
Methods
Whole-exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM-related genes using variant calling and stringent variant filtration process. Subsequently, in silico homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants.
Results
A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients (n = 12/22) in the CMD group and 35% patients (n = 5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild-type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis.
Conclusion
The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling.
DISCLOSURE OF CONFLICTS OF INTEREST
The authors declare no financial or other conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The FASTQ files have been uploaded to the European Nucleotide Archive and the accession number is PRJEB34933.
Supporting Information
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| ene14616-sup-0001-AppendixS1.docxWord document, 1.6 MB |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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