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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1067-1074
 

The clinical diagnostic utility of array CGH in children with syndromic microcephaly


1 Department of Pediatrics, Centre of Rare Diseases, SMS Medical College, Jaipur, Rajasthan, India
2 CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
3 School of Life Sciences, Jaipur National University, Jaipur, Rajasthan, India

Date of Submission25-Feb-2022
Date of Decision06-May-2022
Date of Acceptance20-Jun-2022
Date of Web Publication17-Nov-2022

Correspondence Address:
Mohammed Faruq
CSIR-Institute of Genomics and Integrative Biology, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_202_22

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   Abstract 


Background: A prospective study using array CGH in children with Syndromic microcephaly from a tertiary pediatric healthcare centre in India. Aim: To identify the copy number variations causative of microcephaly detected through chromosomal array CGH. Patients and Methods: Of the 60 patients, 33 (55%) males and 27 (45%) females who consulted the Rare Disease Clinic at Department of Pediatrics, SMS Medical College, Jaipur, with developmental delay/facial dysmorphism/congenital anomalies in combination with microcephaly were included. Exclusion Criteria: Children with acquired or non-genetic causes of microcephaly, craniosynostosis, metabolic diseases, known chromosomal aneuploidy such as trisomy 21, 13, and 18 and abnormal karyotype were excluded. The cohort was analyzed by array CGH in order to identify potentially pathogenic copy number variants (CNVs). Results: Clinically relevant pathogenic or likely pathogenic copy number variations (CNVs) were identified in 20/60 (33.3%) patients, variant of uncertain significance (VOUS) in 4/60 (6.6%) cases and benign CNVs in 3/60 (5%) of total cases. Out of 20 cases with pathogenic CNVs, 12 (60%) patients detected with a deletion, five (25%) patients with duplication and three (15%) patients resulted with a complex chromosomal rearrangement. Twelve cases present CNVs containing genes known to be implicated in microcephaly etiology. Conclusion: This research highlights the contribution of submicroscopic chromosomal changes in the etiology of microcephaly in combination with developmental delay/facial dysmorphism/congenital anomalies (syndromic microcephaly). Our studies provide more insights into the benefits derived by using array CGH analysis in patients with syndromic microcephaly.


Keywords: Array CGH, chromosomal microdeletion, copy number variations, microcephaly, microduplication


How to cite this article:
Goyal M, Faruq M, Gupta A, Shrivastava D, Shamim U. The clinical diagnostic utility of array CGH in children with syndromic microcephaly. Ann Indian Acad Neurol 2022;25:1067-74

How to cite this URL:
Goyal M, Faruq M, Gupta A, Shrivastava D, Shamim U. The clinical diagnostic utility of array CGH in children with syndromic microcephaly. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1067-74. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1067/361416





   Introduction Top


Microcephaly is defined by the measurement of head circumference that is more than 2 standard deviations below the mean or less than the 3rd percentile for the age and sex.[1] Incidence rate of congenital microcephaly has been estimated between 0.58 and 1.87 per 10,000 live births worldwide.[2] The pooled prevalence rate of 2.3 per 10,000 live births has been reported in India.[3] Microcephaly can be classified as congenital (present at birth) or acquired/postnatal (develop later in life) on the basis of time of onset. Both categories (congenital and acquired) can be due to genetic or non-genetic factors. Genetic causes include genetic alterations such as chromosomal aberrations, known microdeletions or duplications syndrome, inherited autosomal recessive microcephaly, and metabolic diseases. Syndromic microcephaly includes neurological dysfunctions and/or dysmorphic features along with multiple congenital anomalies as presenting features.[4]

Diagnostic evaluation and confirmation of microcephaly is essential to determine the associated conditions, prognostication and aid with preconceptional counselling. Genetic testing is the new frontier in evaluating the etiology of microcephaly. Conventional karyotype by culture and banding techniques is unable to detect smaller structural rearrangements of chromosomes which are less than one band (5–10 Mb). Recent technologies such as high resolution array comparative genomic hybridization (array CGH) has been identified as first line investigation in patients with developmental delay (DD)/intellectual disability (ID)/autistic behavior and or facial dysmorphism (FD) and leads to the discovery of many more deletion / duplication syndromes, not identified by conventional G banded karyotype.[5] However, little is known about copy number variations (CNVs) causative of microcephaly.

Hereby, we report the Indian experience, from a cohort of 60 children presented with syndromic microcephaly with DD by array CGH to identify CNVs and to correlate the genetic imbalance with the clinical phenotype.


   Method Top


Sixty Indian children who consulted the Rare Disease Clinic at Department of Pediatrics, SMS Medical college, Jaipur, with DD/FD/congenital anomalies in combination with microcephaly were included in this study. Non syndromic cases of microcephaly with cortical malformation were not included.

The study was carried out from July 2018 to June 2020. The cohort included 33 male and 27 female patients aged till 18 years. At the time of examination, 23.3% were less than 12 months in age, 53.4% between 1 and 5 years and 23.3% were older than 5 years (5–18 years). In our study, 6.7% of children with microcephaly had history of consanguineous marriage of their parents, whereas in majority (93.3%) of the cases parents had of non-consanguineous marriage. The clinical details of all 60 patients included in the study are summarized in the [Supplementary Table S1].



Children with acquired or non-genetic causes of microcephaly, craniosynostosis, metabolic diseases, numerical known chromosomal aneuploidy such as trisomy 21, 13, and 18 and patients with abnormal karyotype were excluded. Clinical evaluations including detailed clinical and developmental history as well as physical examinations were done by a clinical geneticist. The study was approved by the Institutional Ethical Committee. Written informed consent was obtained from parents of all patients for genetic testing.Blood sample was collected in Ethylenediamine tetra acetic acid (EDTA) vial.

Chromosomal array-CGH

Genomic deoxyribonucleic acid (DNA) was extracted from whole blood according to a standard salting out procedure.[6] Array CGH analysis was performed using Cytoscan 750 K for 42 cases and Agilent Sure Print G3 Human CGH 60 k Microarray Kit (Agilent Technologies, Santa Clara, CA, USA) in 18 cases. The version of cytogenomics software used was 4.0. The complete protocol for DNA hybridization and scanning was carried out as per the manufacturer's protocol and data was analyzed using Feature extraction software and cytogenomics software (Agilent Technologies, Santa Clara, CA, USA)/Software Affymetrix Chromosome Analysis Suite (ChAS). The analysis was based on the Human reference genome (GRCh37/hg 19).

The clinical relevance of observed chromosomal aberrations was interrogated on databases such as Online Mendelian Inheritance in Man (OMIM), PUBMED, Database of Genomic variants (http://dgv.tcag.ca/dgv/app/home), DECIPHER (https://decipher.sanger.ac.uk/) for assessing their possible clinical significance. Detected CNVs were classified into the following three groups: Pathogenic (when found to have clinical relevance), variant of uncertain clinical significance (VOUS) (de novo CNVs with no OMIM genes or genes associated with diseases) and Benign (common findings reported in the general population and without relevant gene content) according to the American College of Medical Genetics and Genomics (ACMG) guideline.[7]

Further genetic analysis of involved genes in the affected region and genes for autosomal recessive hereditary microcephaly was not performed. The parental testing was possible only in five positive cases due to financial issues.


   Results Top


The array-CGH analysis identified a total of 33 CNVs in a total of 27/60 patients (45%). CNVs were detected in 20/42 (47.6%) cases tested on Cytoscan 750 k whereas in 7/18 (38.8%) cases tested on Agilent 60 k. Clinically relevant pathogenic or likely pathogenic CNVs was found in 20/60 (33.3%) cases, VOUS in 4/60 (6.6%) and benign CNVs in 3/60 (5%) of total cases. We detected 24 pathogenic CNVs in 20 cases. Out of 20 patients who had pathogenic CNVs, twelve had CNVs involving genes known to have causal relationship with microcephaly. The size of all CNVs ranged from 166 kb to 26.5 Mb. The cut-off value for size criterion for CNVs to be considered as potential regions of significance in the present study was kept at 100 kb. Among the 20 patients carrying pathogenic CNVs, 10 harboured common pathogenic CNVs, 6 had rarely reported pathogenic CNVs and 4 were found with more than one pathogenic CNVs, suggesting the presence of a complex rearrangement. Clinical phenotype and array CGH results of these individuals are summarized in [Table 1].
Table 1: Clinical phenotype and array CGH results with clinically relevant pathogenic CNVs

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Common pathogenic CNVs

Common pathogenic CNVs were identified in ten patients, In detail, in patients 13 and 32 a 1p36.33p36.22 deletion was found of 9.6 and 6 Mb, respectively. In two patients, i.e., number 36 and 39, a 22q11.21 deletion causative of Di George syndrome was found. One each case had 7q11.23 deletion (Williams syndrome), 18q22.1q23 (18q deletion syndrome), 15q11.2q13.1deletion (Angelman syndrome), 5p deletion syndrome (Cri-du-chat syndrome), 10q11.22 duplication and 16p13.3 duplication. They had CNV intervals causing known syndrome and microcephaly is reported as one of the clinical feature.

Rarely reported pathogenic CNVs

In six patients, we identified pathogenic genomic imbalances which are rarely reported. These include deletions on 3p26.3p25.3 (case 17), 2q22.2q22.3 (case 24), 6q13q14.3 (case 25) and 12p12.1 (case 30) and duplication on 19p13.3 (case 27) and Xp22.31 region (case 31).

Interestingly, multiple CNVs have been identified in four patients including different deletions and duplications: Case 7–11q24.3q25 deletion (11 OMIM genes) and 2p25.3p24.2 duplication (47 OMIM genes), case 16–15q26.3 deletion (14 OMIM genes) and 3q26.33 duplication (118 OMIM genes), case 19–18q21.31q23 deletion and 18p11.32p11.31 duplication and case 28–duplication of 11q23.3q25 and 22q11.1q11.21 region.

Parental testing was possible only in five positive cases, to establish whether the obtained chromosomal aberration in the proband was de novo or inherited. Four patients (cases 1, 17, 21, and 39) presented a de novo aberration while one abnormality (case 7) was maternally inherited. In remaining cases, parental testing could not be carried out and hence mode of inheritance was not studied due to financial constraints. This is a limitation to the present study.

CNVs with uncertain clinical significance or benign variant [Table 2]
Table 2: Clinical and molecular features of patients with variants of unknown significance

Click here to view


Four patients (cases 6, 22, 34, and 57) were detected with CNVs with uncertain significance for the clinical features observed in the patients [Table 2]. The clinical relevance of the involved genes in the context of patient's phenotype was not matching. Further studies involving parental testing and qPCR assay was not possible due to financial constraint.

Three patients (cases 10, 18, 58) were detected with CNVs already reported in several normal healthy individuals (Database of Genomic variants), thus considering them as benign variants.


   Discussion Top


Array comparative genomic hybridization (Array CGH) is an advanced genetic diagnostic technique for uncovering chromosomal aberrations and genomic rearrangements not detected by G banding karyotype. Array-CGH has the advantage of scanning the whole genome for regions of duplication/or deletion in cases with syndromic microcephaly, allowing for the early management and better prognosis of affected cases. Genetic syndrome such as DiGeorge syndrome, William's syndrome, 1p36 deletion syndrome, Angelman syndrome, or Cri du chat syndrome can be recognized on clinical examination by a trained clinician or a clinical geneticist or dysmorphologist and the abnormal chromosomal microdeletion/duplication region is anticipated. However, there is lack of knowledge in diagnosing correct syndrome among general pediatrician on clinical examination. The aim of our study was to add evidence that array CGH can be a powerful technique in determining the etiology of syndromic microcephaly where chromosomal imbalances (microdeletions/microduplications) are the causal factors.

The use of two different array CGH platforms Cytoscan 750 k and Agilent 60 k in the study established the enhanced diagnostic utility of both the arrays since the CNV detection rate was nearly comparable and hence both can be used as genetic testing protocol for syndromic microcephaly. However, Cytoscan 750 has an advantage of greater coverage due to higher number (1.9 million) of probes and hence is more popular for CNV analysis in clinical settings.

Furthermore, the detection rate in our study was higher than other reported array CGH studies due to the selection bias of our patients in tertiary care centre. However, our results are comparable to those published by Tsoutsou et al.[4] where array-CGH revealed CNVs ranging in size between 15 kb and 31.6 Mb in 25 out of the 53 patients with microcephaly among other phenotypic anomalies. Genes potentially contributing to microcephaly were revealed in 16/53 patients and concluded that array CGH may be considered as an invaluable diagnostic tool in patients with syndromic microcephaly.

We found neurological findings such as hypotonia and seizures in 15% patients. However, correlation with severity of disease was not found. Previous study also did not show any correlation with severity of neurological manifestation (Bolduc et al., 2005).

MRI brain study revealed white matter hyper intensities in 1p36.33 deletion case and delayed myelination in 18q22.1 deletion among positive cases.

The gene content of each CNV was explored in order to identify candidate genes causative for microcephaly, and, accordingly to their involvement, patients with pathogenic variants were divided into two groups.

Group A: Patients with CNVs including genes causative of patient's phenotype as well as of microcephaly

Twelve out of twenty positive cases carried pathogenic CNVs which are already described as known syndromes with microcephaly as a presenting feature along with other distinct clinical manifestations- DiGeorge syndrome, William's syndrome, 18q deletion syndrome, 1p36 deletion syndrome, Angelman syndrome, Cri du chat syndrome, 2q22.2 deletion.

Two patients (case 36 and case 39) were detected with Di George syndromic region (OMIM # 188400). This region includes the RANBP1 gene; binding partner for Ran GTPase-binding protein implicated in nuclear/cytoplasmic trafficking that participates in the regulation of cell cycle and further, may contribute to the microcephalic phenotype as it is expressed maximally during forebrain patterning and neurogenesis.[8],[9]

Case 21 had microcephaly, FD and pulmonary stenosis and presented a deletion responsible for William syndrome (OMIM #194050). The deletion encompassed about 29 genes including GTF2I gene. GTF2I and GTF2IRD1 genes, encode TFII-I family transcription factors that contributed William syndrome specific FD including microcephaly and cognitive delay.[10],[11]

In patient 43, a 11.8 Mb deletion at 18q22.1q23 was detected, that matches 18q deletion syndrome (OMIM # 601808) characterized by features as in our case [Table 1]. The carried deleted region contained 44 genes including RTTN gene. A mutation in the RTTN genes is known to cause aberrant ciliary function with abnormal development and organization of the human cerebral cortex and have been reported in association with microcephaly, and malformations of cortical development.[12],[13]

The 1p36 deletion syndrome (OMIM # 607872) was detected in cases 13 and 32. Both had clinical features of DD, microcephaly and FD. Echocrdiography revealed ventricular septal defect and white matter hyperintensities in MRI brain of case 32. 1p36 deletions syndrome lacked SKI and CHD5 genes which might have played a contributory role in small brain size. SKI gene is a transcriptional regulator with a dynamic expression pattern during cortical development. SKI-deficient cortices' phenotype includes disturbed timing of neurogenesis, misspecification of projection neurons, and altered cell cycle of neural progenitors.[4] CHD5 gene has a role in chromatin remodeling and gene transcription. It is highly expressed in neurons.[14]

Case 60 showed 5.6 Mb deletion at cytoband 15q11.2q13 and is known to cause Prader Willi syndrome/Angelman syndrome. Loss of maternal copy of the imprinted UBE3A gene at 15q11.2q13 is the causal factor for Angelman syndrome whereas deletion of the paternal copy of the imprinted SNRPN and NDN genes causes Prader–Willi syndrome. Our proband had features suggestive of Angelman syndrome (OMIM #105830). This region also includes MAGEL2 gene, whose loss of function causes abnormalities in brain development and dysmorphic features.[15]

Array CGH revealed 979 kb duplication at 19p13.3 region including 37 genes in case 27. 19p13.3 duplication syndrome is associated with intrauterine growth restriction, DD, ID, hypotonia, feeding difficulties, microcephaly, and FD described in our case [Table 1]. Rarely, cardiac problems, skeletal malformations, and early-onset puberty were reported.[16] The EFNA2 gene encodes a protein member of the ephrin family receptors which comprise the receptor protein-tyrosine kinases and have been implicated in mediating developmental events of the nervous system. The signalling pathway regulates biological processes during embryonic development and guide axon growth cones, which could contribute to the small head circumference.[4],[17]

Case 1 was carrying the deletion described in patients with 5p deletion syndrome/Cri-du-chat syndrome (OMIM #123450) characterized by DD, ID, growth delay, microcephaly, distinctive facial features (round face, hypertelorism, micrognathia, epicanthal folds), and high-pitched monotonous cat-like cry.[18] Deleted region encompassed 76 genes in our case. SEMAF and CTNND2 genes are involved in brain development and associated with mental retardation. CDH18, CDH10, and CDH9 genes play a specific role in synapse formation and axonal growth and are expressed strongly in the brain could be causative of smaller head size.[4]

A 10.2 Mb deletion of the 3p26.3 - p25.3 regions, involving the 3p deletion syndrome (OMIM #613792) critical region, was detected in patient 17. Our case showed similar features of 3p deletion syndrome as the previously reported case, without ocular or cardiac anomalies.[19] The critical region contains 70 genes including BRPF1 and SETD5. Previous work has established that disruption of SETD5 is involved in the cognitive phenotype of this 3p25 syndrome.[20]

Patient 28 showed abnormalities with co-occurrence of microduplication at 11q23.3q25 region and 22q11.1q11.21 genomic regions. There are 198 genes in the duplicated region including BACE1 and FEZ1 genes. BACE1 is related with nervous system development.[21],[22] The duplication of 22q11.1-22q11.21 involves the same region as that deleted in Di George syndrome.

Case 24 detected with 2q22.2q22.3 deletion including ZEB2 gene. Intragenic mutations and deletion in the ZEB2 gene have been described to cause Mowet Wilson syndrome (MWS). MWS is a rare genetic disorder characterized by DD, severe ID, distinctive FD and multiple congenital abnormalities seizures, growth retardation with microcephaly, and chronic constipation without Hirschsprung disease. ZEB2 gene seems to play a crucial role in the embryonic development of neural structures and neural crest.[23]

Group B: Patients with CNVs including genes causative of patient's phenotype except for microcephaly

In our cohort, eight patients' phenotypes match with previously described patients also for microcephaly, attesting that the loci involved by CNVs have a role in the etiology of microcephaly. However, based on current literature data no genes with a clear role in the etiology of microcephaly were identified, thus not excluding the relevance of these genomic regions for microcephaly. The contribution of many genes rather than single gene probably played a role in the etiology of microcephaly and overall phenotype of patients.

A 17.7 Mb duplication of 2p25.3p24.2 region (47 OMIM genes) was detected in addition to a 4.6 Mb deletion of 11q24.3q25 containing 11 OMIM genes in patient 7, inherited from maternal balanced translocations. Her mother was phenotypically normal. This deleted region falls in Jacobsen syndrome region which is a contiguous gene deletion syndrome. Ji et al. described two patients with severe DD, microcephaly, FD and without thrombocytopenia at the time of diagnosis. Structural brain malformation and congenital heart disease was present in one patient carrying a large 12.8 Mb deletion at chromosome 11q23.3-q25. Our case had 4.6 Mb deletion with normal MRI brain, similar to the other case reported by Ji et al.[24] with 4.1 Mb deletion without brain abnormalities.

Case 19 showed 4.2 Mb gain of 18p11.32p11.31 cytoband accompanied by 23.7 Mb losses at 18q21.31q23 region. The patient, a 2-year-old girl had mild dysmorphic features, cleft palate and atrial septal defect. Her cognitive and motor skills were delayed. The parental karyotype was normal. The patient presented with some common features of 18p duplication and 18q deletion including ID and growth retardation, in addition with some features of 18q deletion including short stature, microcephaly, palatal defects, and cardiac defect.[25]

A CNV deletion of 166 kb was detected at 12p12.1 region including SOX5 gene in case 30.Clinical features of 12p deletion syndrome included DD or ID, speech delay, behavioral problems, strabismus, mild dysmorphic features, brain anomalies, seizures, and genital anomalies.[26] SOX5 gene encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system.[27] The disruption of SOX5 gene may contribute to global delay, with prominent expressive language impairment. Haploinsufficiency of SOX5 gene does not seem to have a role in smaller brain size.

Case 25 was presented with hypotonia, microcephaly, dysmorphic facial features, and ventricular septal defect and revealed a 10.2 Mb deletion at 6q13q14.3, which has been published. 42 candidate genes were included in this region. Although the present case had microcephaly, yet both microcephaly and macrocephaly have been reported with 6q11-q14 deletion.[28],[29]

Case 54 showed a 1.4 Mb duplication at 10q11.22 region included 21 genes. Chromosome 10q duplication is a very rare rearrangement consisting of mild to moderate delay in development, postnatal growth retardation, microcephaly, facial features (prominent forehead, small and deep set eyes, epicanthus, upturned nose, bowshaped mouth, micrognathia, abnormal ears) and long, slender limbs. Duplication of 10q11.22 region includes, a regulator of neurite outgrowth gene GPRIN2 and energy homeostasis gene PPYR1, may be responsible for the DD and ID.[30]

Array-CGH analysis revealed gain at Xp22.31 region including 6 genes (VCX3A, HDHD1, STS, VCX, and PNPLA4 and MIR651) in case 31. None of these genes are reported to be involved in reduced brain size. The duplication of this region has been reported in healthy people as well as in individuals with varying degrees of neurological impairment. Our case overlaps with those previously described phenotype including DD, feeding difficulty, hyperactivity, hypotonia, seizures, dysmorphic facies, and microcephaly.[31]

Case 56 presented a duplication of 16p13.3 region with global DD, absence of speech, low intellect, microcephaly, FD, Sandle gape bilaterally and autistic behavior that has been published.[32] Dysmorphic facial features and ID are because of overexpression of CREBBP gene.[33]

Patients with Variant of uncertain clinical significance (VOUS)

Array CGH also may detect some VOUS variants, which can be difficult to interpret and counsel the parents. Efforts should be made to identify the relevance of VOUS in such disorders to give risk of recurrence.

Patient 6 was detected with 3.8 Mb loss at Xp11.1q11.1 and 0.5 Mb gain at 4q12. 4q 12 regions contain only one gene IGFBP7, mutation causes retinal arterial macroaneurysm with supravascular pulmonic stenosis. Patient 22 showed a gain at Xq21.2, containing 1 OMIM gene, CHM. Mutations in this gene causes choroidermia, characterized by progressive dystrophy of the choroid and retina. Eye evaluation of our case was normal. The clinical relevance of the genes in the context of the patient's phenotype is yet to be established.

The present study has several limitations. First, confirmation of CNVs by qPCR and genetic analysis of involved genes in the affected region and genes for autosomal recessive hereditary microcephaly was not performed due to financial issues. Second, parental genetic tests for determining whether the CNVs were de novo or inherited could not be performed for every case. The parental testing was possible only in five positive cases. Third, diagnostic tests for DD, such as the Bayley Scales and Toddler Development test, were not performed for each patient, although we included patients with gross global DD.


   Conclusion Top


There are various studies describing the extensive application of array-CGH in patients with DD/ID/multiple congenital malformation. However, there are only few studies worldwide showing the diagnostic utility of array CGH in children with syndromic microcephaly. To the best of our knowledge, there is no such study in Indian context. The aim of our study was to add evidence that array CGH is a powerful technique in determining the etiology of syndromic microcephaly where chromosomal imbalances (microdeletions/microduplications) are the causal factors. It also includes the accurate definition of the breakpoints in the deleted/duplicated regions, thus allowing a more precise genotype–phenotype correlation. Further extensive use of advanced technology such as exome sequencing and genome sequencing in patients with syndromic microcephaly will recognize more information regarding candidate genes responsible for small brain size.

To the best of our knowledge, this is the first study reported in Indian patients with syndromic microcephaly.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgments

This work was financially supported by Council of Scientific and Industrial Research (CSIR)-funded GOMED project (MLP1601 and MLP1802).

Financial support and sponsorship

This work was financially supported by Council of Scientific and Industrial Research (CSIR)-funded GOMED project (MLP1601 and MLP1802).

Conflicts of interest

There are no conflicts of interest.



 
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