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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 3  |  Page : 407-416
 

Genetic spectrum of inherited neuropathies in India


1 Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
2 Laboratory of Human Molecular Genetics, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, Telangana, India
3 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
4 Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

Date of Submission21-Mar-2022
Date of Acceptance30-Apr-2022
Date of Web Publication14-Jun-2022

Correspondence Address:
Madhu Nagappa
Additional Professor, Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_269_22

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   Abstract 


Background and Objectives: Charcot-Marie-Tooth (CMT) disease is the commonest inherited neuromuscular disorder and has heterogeneous manifestations. Data regarding genetic basis of CMT from India is limited. This study aims to report the variations by using high throughput sequencing in Indian CMT cohort. Methods: Fifty-five probands (M:F 29:26) with suspected inherited neuropathy underwent genetic testing (whole exome: 31, clinical exome: 17 and targeted panel: 7). Their clinical and genetic data were analysed. Results: Age at onset ranged from infancy to 54 years. Clinical features included early-onset neuropathy (n=23), skeletal deformities (n=45), impaired vision (n=8), impaired hearing (n=6), facial palsy (n=8), thickened nerves (n=4), impaired cognition (n=5), seizures (n=5), pyramidal signs (n=7), ataxia (n=8) and vocal cord palsy, slow tongue movements and psychosis in one patient each. Twenty-eight patients had demyelinating electrophysiology. Abnormal visual and auditory evoked potentials were noted in 60.60% and 37.5% respectively. Sixty two variants were identified in 37 genes including variants of uncertain significance (n=34) and novel variants (n=45). Eleven patients had additional variations in genes implicated in CMTs/ other neurological disorders. Ten patients did not have variations in neuropathy associated genes, but had variations in genes implicated in other neurological disorders. In seven patients, no variations were detected. Conclusion: In this single centre cohort study from India, genetic diagnosis could be established in 87% of patients with inherited neuropathy. The identified spectrum of genetic variations adds to the pool of existing data and provides a platform for validation studies in cell culture or animal model systems.


Keywords: Charcot-Marie-Tooth Disease, genetic modifiers, MFN2, next-generation sequencing, novel variations, SH3TC2


How to cite this article:
Sharma S, Govindaraj P, Chickabasaviah YT, Siram R, Shroti A, Seshagiri DV, Debnath M, Bindu PS, Taly AB, Nagappa M. Genetic spectrum of inherited neuropathies in India. Ann Indian Acad Neurol 2022;25:407-16

How to cite this URL:
Sharma S, Govindaraj P, Chickabasaviah YT, Siram R, Shroti A, Seshagiri DV, Debnath M, Bindu PS, Taly AB, Nagappa M. Genetic spectrum of inherited neuropathies in India. Ann Indian Acad Neurol [serial online] 2022 [cited 2022 Aug 14];25:407-16. Available from: https://www.annalsofian.org/text.asp?2022/25/3/407/347482





   Introduction Top


Inherited neuropathies are a heterogeneous group of diseases that predominantly affect the peripheral nerves but may be associated with other features such as spasticity, ataxia, global developmental delay, etc., resulting in complex syndromes.[1] These are slow-progressive disorders characterized by distal symmetrical weakness of the limbs, hypo/areflexia, and skeletal deformities that are more pronounced in the lower limbs.[2],[3] They commonly begin in the first two decades of life, cause progressive disability, and impair quality of life.[4],[5] They are broadly categorized on the basis of electrophysiological studies as: (a) demyelinating with predominant involvement of peripheral myelin wherein nerve conduction velocities are reduced, and (ii) axonal with predominant involvement of peripheral nerve axons wherein amplitudes of compound muscle action potentials are reduced with normal or slightly reduced nerve conduction velocities.

Among the inherited neuropathies, the hereditary motor and sensory neuropathies (HMSNs) or Charcot-Marie-Tooth diseases (CMTs) constitute the most frequent genetically determined neuromuscular disorders.[6] They are caused by mutations in genes encoding proteins involved in different peripheral nerve functions such as maintenance and compaction of myelin in Schwann cells, axonal transport, as well as mitochondrial metabolism and dynamics.[7] Progress in the field of genomics with the advent of the next generation sequencing (NGS) technology has led to the identification of a number of genes involved in various subtypes of CMTs in different ethnic groups across the globe.[3],[8],[9],[10] Identifying the molecular genetic abnormality establishes the diagnosis as well as aids in the treatment and reproductive planning.

India is a home to about one-sixth of the world population which is ethnically diverse, and has a distinct genetic landscape. Hospital based audits suggest that hereditary neuropathies account for 4.8% of all neuropathies.[11] Data on genetics of CMTs from India are rather limited.[12],[13] This study is aimed to identify variants in disease-associated genes using high throughput sequencing in a cohort of CMT from India.


   Patients and Methods Top


This study was carried out at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Probands were recruited from a single neurology unit between March 2017 and February 2020, after obtaining written informed consent. They included subjects with chronic progressive sensorimotor neuropathy of suspected genetic etiology who did not have evidence of alternative etiologies such as acquired, autoimmune, or metabolic causes. Patients with duplication or point mutations in the PMP22 gene were published earlier and have not been included in the present study.[13] The clinical data included age, gender, symptom–duration, type of neuropathy, and sites of neuraxis affected. The functional/ambulatory status of the patients was objectively quantified using the CMT neuropathy score (CMTNS) and the modified Rankin Score (mRS).[14],[15] Nerve conduction studies were carried out using standard protocols at a laboratory temperature of 32–34°C (Neuropack S1 MEB-9400K, Nihon Kohden Corporation, Tokyo, Japan). Three motor nerves (median, ulnar, and common peroneal nerves) and three sensory nerves (median, ulnar, and sural nerves) were examined. Conduction blocks were considered if the ratio of the amplitudes of compound muscle action potentials following proximal and distal stimulation was <0.5, provided the distal amplitude was at least 20% of the lower limit of normal.[16] Recordings of evoked potentials to visual and auditory stimuli were carried out wherever possible. The study was approved by the Institute Ethics Committee of NIMHANS.

Genomic DNA was extracted using standard phenol–chloroform method from about 6 mL of peripheral blood collected in an ethylenediaminetetraacetic acid (EDTA)-coated vacutainer. Genetic analysis was carried out using NGS (whole exome: 31, clinical exome: 17, and targeted panel: 7). The libraries were prepared, followed by enrichment as per manufacturer's instruction for sequencing with 80-100X denotes the coverage of the exonic regions. The sequences obtained were aligned to the human reference genome (GRCh37/hg19) and analyzed using Sentieon for removing duplicates, recalibration, and re-alignment of indels. Sentieon haplotype caller was used to identify variants relevant to the clinical phenotype.[17] Common variants were filtered based on allele frequency in 1000Genome Phase 3, ExAC (v1.0), gnomAD (bv2.1), EVS, dbSNP (v151), and 1000 Japanese Genome.[18],[19],[20],[21] The identified variants were interpreted based on the recommendations of American College of Medical Genetics and Genomics (ACMG).[22] The pathogenicity of the identified variants was predicted using multiple tools namely PolyPhen-2, sorting intolerant from tolerant (SIFT), and mutation taster. The data were entered in a predesigned proforma and incorporated into a Microsoft Excel Spreadsheet for analysis.


   Results Top


The current cohort comprised of 55 patients. The age at evaluation ranged from 2 to 72 years. The clinical and electrophysiological characteristics of patients are summarized in [Table 1]. In the present study, 62 variants were identified in 37 genes in these 55 probands. They included pathogenic/likely pathogenic variants (n = 28) and variants of uncertain significance (n = 34). There were 17 reported and 45 novel variants. Of these, eight patients had variants in more than one gene (MFN2+SBF, SH3TC2+AARS, SH3TC2+JPH 1, SH3TC2+UBQLN2, FGD4+WNK1, MARS+SBF2, MPZ+DNMT1, and GARS+GAN) implicated in the neuropathy phenotype. Three patients had additional variants in genes that so far have not been associated with neuropathy (DCTN1+BLK, IGHMBP2+SLC12A6, and MFN2+VPS13D). Ten patients did not have variants in neuropathy associated genes, but had variants in genes such as ATM, SETX, COX15, MPV17, OPA1, SACS, C10ORF2, APOB, and CDH23 which are implicated in other neurological disorders. In seven patients, no variants were detected [Table 2] and [Table 3]. In silico analysis showed that the detected variants were damaging [Supplementary Table 1].
Table 1: Clinical and electrophysiological characteristics of the current cohort of inherited neuropathy (N=55)

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Table 2: Summary of genetic analysis of patients with inherited neuropathy included in the present cohort

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Table 3: Genetic abnormalities identified in the present cohort of patients with inherited neuropathies (n=55)

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   Discussion Top


This study led to the identification of pathogenic/likely pathogenic variants in 87.3% cases, in addition to a number of novel variants as well as variants of uncertain significance (VUS). However, in other cohorts the detection rates ranged from 24% to 87% based on high throughput sequencing.[38],[39],[40] The clinical, demographic, and genetic features in various cohorts of CMT are compared with the present study [Supplementary Table 2].[87] Previous studies have shown that variants in PMP22, GJB1, MPZ and MFN2 genes account for vast majority of the CMTs.[9],[41] Variants in other genes though individually rare, constitute a large number, with nearly 100 genes being implicated in the pathogenesis of CMT.[42] Given the large number of genes implicated in CMT, it may be difficult to precisely pinpoint the genetic abnormality based on the phenotype, because of significant overlapping clinical features. For instance, vocal cord palsies have been described in both axonal and demyelinating neuropathies due to MFN2, GDAP1, TRPV4, SH3TC2, and MTMR2 mutations.[43] Sensorineural hearing loss (SNHL) has also been reported in demyelinating and axonal CMT due to PMP22, GJB1, MPZ, PRPS1, and SH3TC2 mutations, among others.[44],[45],[46],[47] We used NGS to identify the genetic basis in patients of Indian origin with suspected inherited neuropathies in whom the PMP22 variants had been excluded. The most frequent abnormality in the present study was in the MFN2 gene (all pathogenic/likely pathogenic), which is similar to that noted in the previous studies. MFN2 is reported to be the commonest cause of axonal CMT followed by MORC2.[48] In the present study, no variants in MORC2 were identified. Variants in SH3TC2 were the second most frequent abnormality in the present cohort (pathogenic/likely pathogenic = 3, VUS = 4), which is reported to be the commonest cause of recessively inherited demyelinating CMT.[49],[50] Variants in GJB1 and MPZ were identified in four and two patients, respectively. An interesting finding in the present cohort is that a proportion of patients had conduction blocks on electrophysiological testing. Classically, demyelination in CMT is considered to be uniform and conduction block is generally not expected in electrophysiological testing. However, while in the “pre-genetic” era it was believed that inherited neuropathies have uniform reduction in conduction parameters, there is growing evidence that some of the CMTs may exhibit non-uniform conduction abnormalities as well as conduction blocks. In fact, conduction block and non-uniform slowing can form the basis for targeted genetic testing (e.g., X-linked CMT).[51]



In the present study, in addition to the common genes (GJB1, MPZ, and MFN2), variants were identified in a number of genes implicated in various cellular functions such as growth and differentiation (SBF1, DCTN1), endocytosis (SH3TC2, LRSAM1), tRNA synthetases (AARS, MARS, GARS), intracellular calcium homeostasis (JPH 1), ubiquitin-proteasome system (UBQLN2, GAN), actin cytoskeleton regulation (FGD4), DNA repair (SETX, ATM), transcriptional regulation (IGHMBP2, DNMT1), protein homeostasis (MME, HSPB8), mitochondrial function including dynamics and maintenance (MPV17, COX6A1, COX15, VPS13, OPA1, C10ORF2), and ion transport (SLC12A6). Besides these, alterations in endoplasmic reticulum structure (TFG, ATL1), membrane or vesicle trafficking (LITAF, SBF1, DNM2, FIG4), myelin structural organization (PRX), axonal cytoskeleton maintenance (NEFL, NEFH), and axonal transport (KIF1, DCTN1, SPG11) have been reported from other cohorts of HMSN.[66],[67]

The CMTs may follow autosomal or X-linked, dominant or recessive pattern of inheritance. Homozygous or compound heterozygous variants in the “dominantly” inherited genes resulting in recessive CMTs with early onset and more severe disability have been reported. For example, MFN2 is usually linked to autosomal dominant (AD) inheritance but autosomal recessive (AR, homozygous or compound heterozygous variants) pattern is also reported where the proband inherits one mutation from each parent. The heterozygous parents can be asymptomatic or may manifest with late-onset milder phenotype, in contrast to early-onset severe phenotype in the proband bearing two mutations.[68],[69] We also report two homozygous variants in MFN2 in three subjects with early-onset neuropathy [Patients 5–7, [Table 3]]. In contrast to compound heterozygous variants that occur in trans, distantly spaced double variants in cis have also been reported uncommonly in MFN2.[70],[71] Likewise, LRSAM1 variants are dominantly inherited and are associated with CMT2 phenotype with onset in the second decade of life and moderate disability.[72] In the present study, patient 32 had early-onset neuropathy with severe disability and two heterozygous variants in LRSAM1. The presence of two variants might have contributed to the increased disease severity. This phenomenon may be comparable to severe phenotypes associated with homozygous/compound heterozygous mutations in MFN2.

The present study identified variants in multiple genes in 11 patients. There are a few reports highlighting co-occurrence of variants of multiple genes in the same individual with CMT.[73],[74],[75],[76],[77],[78] Such variants are often inherited not only from heterozygous carrier parents, but can also occur de novo. High throughput sequencing permits unbiased analysis of several genes and helps in identifying all the variants which could have been missed in sequential analysis. Traditional sequencing of genes in tandem does not extend testing for other genes once a genetic variant that explains the phenotype is identified. Using NGS one can identify multiple genetic variants in different combinations: (a) more than one CMT-associated genes, or (b) CMT-associated gene(s) implicated in other neurodegenerative disorders. Two variants identified in different neuropathy-related genes may cause mild phenotype when they occur in isolation, but when present together may have additive effect on severity of symptoms by causing pathology at different sites. The non-neuropathy related genetic variants may act as modifier when present together with another gene known to cause neuropathy.[77] The most common cause of demyelinating CMT, that is, PMP22 duplication has been reported with additional dose of PMP22 (triplication) resulting in more severe clinical phenotype.[79],[80] There are reports on PMP22 mutation along with other related genes like LITAF, SMN2, DCTN1, GJB1, FSHD, and ABCD1 [Supplementary Table 3].[73],[74],[75],[76] Coexistence of variants in MFN2 and GDAP1 in axonal CMT has also been reported. The two variants act in a synergistic manner resulting in major mitochondrial defects as each gene is involved in mitochondrial bioenergetics either for adenosine triphosphate (ATP) production or respiratory chain complex I activity.[81],[82],[83],[84] Apart from PMP22 and MFN2, there are selected reports on other gene combinations such as JPH 1/GDAP1 and EGR2/GJB1.[55],[77],[85] Increased genetic “burden” arising from this combination of genetic mutations may contribute to phenotypic variability including age at onset and disease severity.[78] Based on the available literature, we hypothesize that the co-occurence of multiple genetic variants may have impacted the clinical phenotype including the severity in the present cohort. However, we did not establish the synergy between the multiple variants and their impact on the phenotypes by using in vitro studies or animal models. This is a limitation of the present study.



The present study identified a number of novel variants and VUS which require to be validated for confirming their pathogenicity. Previous studies have also reported a large number of VUS, ranging from 10 to as high as 215 in a single cohort.[56],[86] Reporting of VUS is dependent on the ACMG guidelines. Validating individual variants in various genes may not be an efficient approach given the low frequency of individual genetic variants other than PMP22, MPZ, GJB, and MFN2 genes. Due to the prevailing high levels of genetic heterogeneity, narrowing down to common cellular pathways through network biology approach and forming “disease modules” may prove to be more useful in understanding the pathobiology even in patients who are “negative” for genetic abnormalities by whole exome sequencing (WES). Various genes reported in the context of hereditary neuropathies act on interconnected pathways and share common proteins to carry out the overlapping biological functions. The peripheral nervous tissue being highly metabolically active needs constant maintenance of a pool of proteins and other molecular interactors. Mutations in any one of the associated genes resulting in abnormal protein can have a cascading effect on the protein interactome and may fail to maintain the cellular homeostasis. This effect is propagated along the nerve function adding to disease pathology. These networks of proteins and their molecular partners can be exploited further to understand the disease pathogenesis and further translated for drug development and therapeutics.[52]

In conclusion, we report the NGS findings in a fairly large cohort of patients with inherited neuropathies from India and highlight the spectrum of genetic abnormalities. This study brings out a number of novel variants and VUS. Establishing an accurate genetic diagnosis is important not only for genetic counseling but also in the perspective of including patients for upcoming therapeutic trials. NGS identified variants in several genes, including those that have pathobiological significance in neuropathy and other non-neuropathic disorders. The functional validation of novel variants and the impact of their interactions with other molecular partners remain to be established in future studies.

Financial support and sponsorship

The study was funded by a grant to Dr Madhu Nagappa from the Indian Council of Medical Research (BMS/TF/Trans-Neuro/2014-3389/July-15/16/KA/Govt dated 25th July 2016).

Conflicts of interest

There are no conflicts of interest.



 
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