EDITORIAL COMMENTARY Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 991-992  

The expanding genetic landscape of charcot-marie-tooth diseases (CMTs): An indian perspective

Nirav Sanghani
Staff Physician, Department of Neurology, St Francis Hospital and Medical Center, Hartford; Assistant Professor, Department of Neurology, University of Connecticut School of Medicine, Farmington; Assistant Professor, Department of Medicine, Frank H. Natter MD School of Medicine, Quinnipiac University, Hamden, CT, USA

Date of Submission18-Aug-2022Date of Decision23-Aug-2022Date of Acceptance25-Aug-2022Date of Web Publication17-Nov-2022

Correspondence Address:
Nirav Sanghani
Trinity Health of New England, 1000 Asylum Ave, Suite 2112, Hartford, CT - 06105
USA

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/aian.aian_712_22

  How to cite this article:
Sanghani N. The expanding genetic landscape of charcot-marie-tooth diseases (CMTs): An indian perspective. Ann Indian Acad Neurol 2022;25:991-2

Inherited neuropathies are one of the most prevalent neuromuscular disorders, affecting around 1 in 2500 people. Next-generation sequencing (NGS) has become a valuable tool in the diagnosis of inherited neuropathies like Charcot-Marie-Tooth diseases (CMTs). NGS allows multiple parallel sequencing of the whole human genome (whole genome sequencing), their protein-coding sequences [whole exome sequencing (WES)], or specific genes of interest (targeted multigene panels). With advances in NGS and with a better understanding of cellular function, the number of genes implicated in inherited neuropathies has increased substantially in the last decade (more than 100). Although hospital-based studies from India report an incidence of inherited neuropathies of around 5%,[1] the actual incidence seems to be more than that. Sparse data is available regarding the genetics of inherited neuropathies in the Indian subcontinent.[2],[3] The original research study presented by Sharma et al.[4] sheds great light on the genetic spectrum of CMTs in India.

This single-center study included 55 patients with a suspected diagnosis of genetically determined neuropathy, patients with PMP22 deletion and duplications were excluded. The age at presentation varied widely and many of the patients had features other than neuropathy. The authors identified 62 total variants in 37 genes, 45 (73%) were novel and not reported before. The authors also found a high number of variants of uncertain significance (VUS, n = 34). Thirty-eight patients (70%) had variants in CMT-associated genes, the commonest being in MFN2, SH3TC2, and GJB1. Variants were also identified in the genes implicated in other cellular functions including growth and differentiation, endocytosis, tRNA synthetases, intracellular calcium homeostasis, ubiquitin-proteasome system, actin cytoskeleton regulation, protein homeostasis, and mitochondrial function. Eleven patients had variants in more than one CMT-associated genes, and the authors postulated that simultaneous occurrence of more than one variant might have increased “genetic burden” and increased phenotypic severity in those patients. The authors were able to establish a genetic diagnosis in 87% of patients with inherited neuropathy.

This is one of the very few studies describing the genetic spectrum of CMTs in the Indian population. As also seen in the prior studies, the most common variants (apart from PMP22) were found in MFN2, SH3TC2, and GJB1. One of the interesting findings was a high number of novel variants and VUSs. When a variant is novel and not enough data is available regarding its association with the disease, it is classified based on criteria using variant evidence (e.g, population data, computational data, functional data, segregation data, etc.) into five categories: pathogenic, likely pathogenic, VUS, likely benign and benign.[5] For VUS, disease pathogenicity cannot be conclusively demonstrated or excluded based on available data. With advances in NSG, the number of VUS has increased and will continue to increase, making the interpretation more challenging. However, it is possible to reclassify VUS in the future if more data become available.

In the present study, 35 variants in CMT-associated genes were novel, out of which 13 were pathogenic/likely pathogenic. Out of 24 VUS in CMT-associated genes, 7 were found to be damaging or affecting protein structure in all in-silico prediction tests, 13 were damaging in at least one prediction test, 1 was found to be tolerated/benign, and information was not available for 3 VUS [see [supplementary Table 1] in the article].[4]

Except for the limitation of being a single-center study and not representing the diverse ethnic groups from India, this is one of the landmark studies describing the genetic landscape of CMTs in India. Many of novel variants and VUSs found in the study may be seen exclusively in the Indian population. With more such studies, they might be reclassified, and it might also be possible to develop a low-cost targeted genetic panel test for CMTs specifically for Indian patients.

 

   References 
1.Trivedi S, Pandit A, Ganguly G, Das SK. Epidemiology of peripheral neuropathy: An Indian perspective. Ann Indian Acad Neurol 2017;20:173-84.  
[PUBMED]  [Full text]  2.Khadilkar SV, Patil ND, Kadam ND, Mansukhani KA, Patel BA. Clinico-electrophysiological and genetic overlaps and magnetic resonance imaging findings in Charcot-Marie- tooth disease: A pilot study from western India. Ann Indian Acad Neurol 2017;20:425-9.  
[PUBMED]  [Full text]  3.Nagappa M, Sharma S, Govindaraj P, Chickabasaviah YT, Siram R, Shroti A, et al. PMP22 gene-associated neuropathies: Phenotypic spectrum in a cohort from India. J Mol Neurosci 2020;70:778-89.  
    4.Sharma S, Govindaraj P, Chickabasaviah YT, Siram R, Shroti A, Seshagiri DV, et al. Genetic spectrum of inherited neuropathies in India. Ann Indian Acad Neurol 2022;25:407-16.  
  [Full text]  5.Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for molecular pathology. Genet Med 2015;17:405-24.