Emergence of SARS-CoV-2 VOCs at different time points through COVID-19 pandemic raised concern for increased transmissibility, infectivity and vaccination breakthroughs.
1567 international travellers ...plus community transmission COVID-19 cases were analysed for mutational profile of VOCS, that led to notable waves in India, namely Alpha, Delta, and Omicron. Spike mutations in Linkage Disequilibrium were investigated for potential impact on structural and functional changes of Spike-ACE2.
ORF1ab and spike harboured diverse mutational signatures for each lineage. B.1.617.2 and AY. * demonstrated comparable profile, yet non-clade defining mutations were majorly unique between international vs community samples. Contrarily, Omicron lineages showed substantial overlap in non-clade defining mutations, signifying early phase of transmission and evolution within Indian community. Mutations in LD for Alpha N501Y, A570D, D1118H, S982A, Delta P681R, L452R, EFR:156–158 G, D950N, G142D and Omicron P681H, D796Y, N764K, N969K, N501Y, S375F resulted in decreased binding affinity of Spike-ACE2 for Alpha and BA.1 whereas Delta, Omicron and BA.2 demonstrated strong binding.
Genomic surveillance tracked spread of VOCs in international travellers’ vs community transmission. Behavioural transmission patterns of variants, based on selective advantage incurred by spike mutations, led us to predict sudden takeover of Delta over Alpha and BA.2 over BA.1 in India.
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•The mutational landscape of 1567 international travellers and community transmission were characterized across VOCs in India•Mutations in LD for VOCs demonstrated differentially altered binding affinity and electrostatic interactions of Spike-ACE2.•Altered Spike-ACE2 affinity among VOCs predicted sudden takeover of Delta over Alpha and BA.2 over BA.1 in India.
Hexanucleotide repeat expansion in C9orf72 is defined as a major causative factor for familial amyotrophic lateral sclerosis (ALS). The mutation frequency varies dramatically among populations of ...different ethnicity; however, in most cases, C9orf72 mutant has been described on a common founder haplotype. We assessed its frequency in a study cohort involving 593 clinically and electrophysiologically defined ALS cases. We also investigated the presence of reported Finnish haplotype among the mutation carriers. The identified common haplotype region was further screened in 192 (carrying 2–6 G4C2 repeats) and 96 (≥7 repeats) control chromosomes. The G4C2 expansion was observed in 3.2% (19/593) of total cases where 9/19 (47.4%) positive cases belonged to the eastern region of India. Haplotype analysis revealed 11 G4C2-Ex carriers shared the common haplotype (haplo-A) background spanning a region of ∼90 kbp (rs895021-rs11789520) including rs3849942 (a well-known global at-risk loci with T allele for G4C2 expansion). The other 3 G4C2-Ex cases had a different haplotype (haplo-B) with core difference from haplo-A at G4C2-Ex flanking 31 kbp region between rs3849942 and rs11789520 SNPs (allele 'C' of rs3849942 which is a nonrisk allele). Out of other five G4C2-cases, four carried the risk allele T of rs3849942 while one harbored the non-risk allele. This study establishes the prevalence of C9orf72 expansion in Indian ALS cases providing further evidence for geographical predilection. The global core risk haplotype predominated C9orf72 expansion–positive ALS cases, yet the existence of a different haplotype suggests a second lineage (haplo B), which may have been derived from the Finnish core haplotype or may imply a unique haplotype among Asians. The association of risk haplotype with normal intermediate C9orf72 alleles reinforced its role in conferring instability to the C9orf72-G4C2 region. We thus present an effective support to interpret future burden of ALS cases in India.
•Hexanucleotide repeat (G4C2) expansion in C9orf72 is a major causative factor for familial amyotrophic lateral sclerosis (ALS).•Shamim et al. have described 3.2% G4C2 hexanucleotide expansion–positive Indian ALS cases from screening of larger number of patients (n = 593).•Two lineages of G4C2 expansion–associated haplotypes were observed in Indian ALS subjects.
Objective
Information on etiology of congenital nephrotic syndrome in non-Caucasian populations is limited. This study aimed to determine the genetic basis of congenital nephrotic syndrome in Indian ...patients.
Methods
In this observational, cross-sectional study, whole exome sequencing was performed on samples from all children diagnosed with congenital nephrotic syndrome, presenting at centers collaborating in a nationwide registry and biorepository. Analysis was targeted to focus on reported or novel, pathogenic or likely pathogenic variants in 89 genes implicated in etiology of nephrotic syndrome. Sanger sequencing was used to confirm disease-causing variants in patients and allelic segregation of compound heterozygous variants in samples from parents. Inheritance of a shared haplotype was analyzed among ten individuals carrying the most common variant.
Results
During 2017–2019, 34 patients with congenital nephrotic syndrome were screened. Consanguinity and similar illness in siblings were reported in eleven patients each. Homozygous or compound heterozygous, pathogenic or likely pathogenic variants were found in
NPHS1
in 24 cases, including two novel variants. One patient each had homozygous pathogenic or likely pathogenic known or novel variant in
NPHS2, PLCE1, OSGEP
and
LAMB2
genes. Patients with
OSGEP
and
LAMB2
mutations had phenotype typical of Galloway Mowat and Pierson syndromes, respectively. Three variants in
NPHS1
were common to 16 individuals. One reported variant in exon 19 (c.2600G>A; p.Gly867Asp) appears to share a common founder.
Conclusion
A genetic cause was determined for 82.4% patients with congenital nephrotic syndrome. Variants in
NPHS1
are most common in Indian patients and founder mutations might be present.
ABSTRACT
Background
Hypermanganesemia with dystonia 1 and 2 (HMNDYT1 and 2) are rare, inherited disorders of manganese transport.
Objectives
We aimed to describe clinical, laboratory features, and ...outcomes among children with HMNDYT.
Methods
We conducted a retrospective multicenter study involving tertiary centers across India. We enrolled children between 1 month to 18 years of age with genetically confirmed/clinically probable HMNDYT. Clinical, laboratory profile, genetic testing, treatment details, and outcomes scored by treating physicians on a Likert scale were recorded.
Results
We enrolled 27 children (19 girls). Fourteen harbored SLC30A10 mutations; nine had SLC39A14 mutations. The SLC39A14 cohort had lower median age at onset (1.3 interquartile range (IQR), 0.7–5.5 years) versus SLC30A10 cohort (2.0 IQR, 1.5–5.1 years). The most frequent neurological features were dystonia (100%; n = 27), gait abnormality (77.7%; n = 21), falls (66.7%; n = 18), and parkinsonism (59.3%; n = 16). Median serum manganese (Mn) levels among SLC39A14 (44.9 IQR, 27.3–147.7 mcg/L) cohort were higher than SLC30A10 (29.4 17.1–42.0 mcg/L); median hemoglobin was higher in SLC30A10 (16.3 IQR, 15.2–17.5 g/dL) versus SLC39A14 cohort (12.5 8.8–13.2 g/dL). Hepatic involvement and polycythaemia were observed exclusively in SLC30A10 variants. A total of 26/27 children underwent chelation with disodium calcium edetate. Nine demonstrated some improvement, three stabilized, two had marked improvement, and one had normalization. Children with SLC39A14 mutations had poorer response. Two children died and nine were lost to follow‐up.
Conclusions
We found female predominance. Children with SLC39A14 mutations presented at younger age and responded less favorably to chelation compared to SLC30A10 mutations. There is emerging need to better define management strategies, especially in low resource settings.
Epidemiological studies have indicated that populations with high isoflavone intake through soy consumption have lower rates of breast, prostate, and colon cancer. The isoflavone polyphenol genistein ...in soybean is considered to be a potent chemopreventive agent against cancer. In order to explore the chemical basis of chemopreventive activity of genistein, in this paper we have examined the structure-activity relationship between genistein and its structural analogue biochanin A. We show that both genistein and its methylated derivative biochanin A are able to mobilize nuclear copper in human lymphocyte, leading to degradation of cellular DNA. However, the relative rate of DNA breakage was greater in the case of genistein. Further, the cellular DNA degradation was inhibited by copper chelator (neocuproine/bathocuproine) but not by compounds that specifically bind iron and zinc (desferrioxamine mesylate and histidine, respectively). We also compared the antioxidant activity of the two isoflavones against tert-butylhydroperoxide-induced oxidative breakage in lymphocytes. Again genistein was found to be more effective than biochanin A in providing protection against oxidative stress induced by tert-butylhydroperoxide. It would therefore appear that the structural features of isoflavones that are important for antioxidant properties are also the ones that contribute to their pro-oxidant action through a mechanism that involves redox cycling of chromatin-bound nuclear copper.
Abstract
Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy is a non-progressive disorder characterized by distal tremors. Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been ...reported globally with different genetic predispositions of autosomal dominant inheritance with a high degree of penetrance. In south India, Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported in a large cohort of 48 families, in which the genetic defect was not identified. This report pertains to the whole-genome analysis of four individuals followed by repeat-primed PCR for 102 patients from a familial cohort of 325 individuals. All the patients underwent extensive clinical evaluation including neuropsychological examinations. The whole-genome sequencing was done for two affected and two unaffected individuals, belonging to two different families. The whole-genome sequencing analysis revealed the repeat expansion of TTTTA and TTTCA in intron 4 of the SAMD12 gene located on chromosome 8 in the patients affected with Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy, whereas the unaffected family members were negative for the similar expansion. Further, the repeat-primed PCR analysis of 102 patients showed the expansion of the TTTCA repeats in the intron 4 of SAMD12 gene. All patients registered for this study belong to a single community called “Nadar” whose nativity is confined to the southern districts of India, with reported unique genetic characteristics. This is the largest and most comprehensive single report on clinically and genetically characterized Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy patients belonging to a unique ethnic group worldwide.
Mahadevan et al. identified a pentanucleotide (TTTCA)n insertional expansion in intron 4 of the SAMD12 gene as a causal mutation for autosomal dominant cortical tremor, myoclonus and epilepsy in 102 patients, in the largest study of the racial clustering of autosomal dominant cortical tremor, myoclonus and epilepsy in a unique ethnic group in south India.
Graphical Abstract
Graphical Abstract
Mutations in the GMPPB gene affect glycosylation of α-dystroglycan, leading to varied clinical phenotypes. We attempted to delineate the muscle MR imaging spectrum of GMPPB-related Congenital ...Myasthenic syndrome (CMS) in a single-center cohort study.
To identify the distinct patterns of muscle involvement in GMPPB gene mutations.
We analyzed the muscle MR images of 7 genetically proven cases of GMPPB dystroglycanopathy belonging to three families and studied the potential qualitative imaging pattern to aid in clinico -radiological diagnosis in neuromuscular practice. All individuals underwent muscle MRI (T1, T2, STIR/PD Fat sat. sequences in 1.5 T machine) of the lower limbs. Qualitative assessment and scoring were done for muscle changes using Mercuri staging for fibro-fatty replacement on T1 sequence and Borsato score for myoedema on STIR sequence.
All patients were of South Indian origin and presented as slowly progressive childhood to adult-onset fatigable limb-girdle muscle weakness, elevated creatine kinase level, and positive decrement response in proximal muscles. Muscle biopsy revealed features of dystrophy. All patients demonstrated identical homozygous mutation c.1000G > A in the GMPPB gene. MRI demonstrated early and severe involvement of paraspinal muscles, gluteus minimus, and relatively less severe involvement of the short head of the biceps femoris. A distinct proximo-distal gradient of affliction was identified in the glutei, vasti, tibialis anterior and peronei. Also, a postero-anterior gradient was observed in the gracilis muscle.
Hitherto unreported, the distinctive MR imaging pattern described here, coupled with relatively slowly progressive symptoms of fatigable limb-girdle weakness, would facilitate an early diagnosis of the milder form of GMPPB- dystroglycanopathy associated with homozygous GMPPB gene mutation.
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