Publications by authors named "Manisha Goyal"

35 Publications

Different SARS-CoV-2 haplotypes associate with geographic origin and case fatality rates of COVID-19 patients.

Infect Genet Evol 2021 06 26;90:104730. Epub 2021 Jan 26.

bioMérieux, Applied Maths, 13809 Research Blvd., Suite 645, Austin, Texas 78750, USA. Electronic address:

The current pandemic of COVID-19 is caused by the SARS-CoV-2 virus for which many variants at the Single Nucleotide Polymorphism (SNP) level have now been identified. We show here that different allelic variants among 692 SARS-CoV-2 genome sequences display a statistically significant association with geographic origin (p < 0.000001) and COVID-19 case severity (p = 0.016). Geographic variation in itself is associated with both case severity and allelic variation especially in strains from Indian origin (p < 0.000001). Using an new alternative bioinformatics approach we were able to confirm that the presence of the D614G mutation correlates with increased case severity in a sample of 127 sequences from a shared geographic origin in the US (p = 0.018). While leaving open the question on the pathogenesis mechanism involved, this suggests that in specific geographic locales certain genotypes of the virus are more pathogenic than others. We here show that viral genome polymorphisms may have an effect on case severity when other factors are controlled for, but that this effect is swamped out by these other factors when comparing cases across different geographic regions.
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http://dx.doi.org/10.1016/j.meegid.2021.104730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837616PMC
June 2021

Metabolic control of cellular immune-competency by odors in .

Elife 2020 12 29;9. Epub 2020 Dec 29.

Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, India.

Studies in different animal model systems have revealed the impact of odors on immune cells; however, any understanding on why and how odors control cellular immunity remained unclear. We find that employ an olfactory-immune cross-talk to tune a specific cell type, the lamellocytes, from hematopoietic-progenitor cells. We show that neuronally released GABA derived upon olfactory stimulation is utilized by blood-progenitor cells as a metabolite and through its catabolism, these cells stabilize Sima/HIFα protein. Sima capacitates blood-progenitor cells with the ability to initiate lamellocyte differentiation. This systemic axis becomes relevant for larvae dwelling in wasp-infested environments where chances of infection are high. By co-opting the olfactory route, the preconditioned animals elevate their systemic GABA levels leading to the upregulation of blood-progenitor cell Sima expression. This elevates their immune-potential and primes them to respond rapidly when infected with parasitic wasps. The present work highlights the importance of the olfaction in immunity and shows how odor detection during animal development is utilized to establish a long-range axis in the control of blood-progenitor competency and immune-priming.
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http://dx.doi.org/10.7554/eLife.60376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808736PMC
December 2020

Retrospective Definition of PCR Ribotypes on the Basis of Whole Genome Polymorphisms: A Proof of Principle Study.

Diagnostics (Basel) 2020 Dec 12;10(12). Epub 2020 Dec 12.

Department of Medical Microbiology and Immunology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA.

is a cause of health care-associated infections. The epidemiological study of infection (CDI) traditionally involves PCR ribotyping. However, ribotyping will be increasingly replaced by whole genome sequencing (WGS). This implies that WGS types need correlation with classical ribotypes (RTs) in order to perform retrospective clinical studies. Here, we selected genomes of hyper-virulent strains of RT001, RT017, RT027, RT078, and RT106 to try and identify new discriminatory markers using in silico ribotyping PCR and De Bruijn graph-based Genome Wide Association Studies (DBGWAS). First, in silico ribotyping PCR was performed using reference primer sequences and 30 genomes of the five different RTs identified above. Second, discriminatory genomic markers were sought with DBGWAS using a set of 160 independent genomes (14 ribotypes). RT-specific genetic polymorphisms were annotated and validated for their specificity and sensitivity against a larger dataset of 2425 genomes covering 132 different RTs. In silico PCR ribotyping was unsuccessful due to non-specific or missing theoretical RT PCR fragments. More successfully, DBGWAS discovered a total of 47 new markers (13 in RT017, 12 in RT078, 9 in RT106, 7 in RT027, and 6 in RT001) with minimum q-values of 0 to 7.40 × 10, indicating excellent marker selectivity. The specificity and sensitivity of individual markers ranged between 0.92 and 1.0 but increased to 1 by combining two markers, hence providing undisputed RT identification based on a single genome sequence. Markers were scattered throughout the genome in intra- and intergenic regions. We propose here a set of new genomic polymorphisms that efficiently identify five hyper-virulent RTs utilizing WGS data only. Further studies need to show whether this initial proof-of-principle observation can be extended to all 600 existing RTs.
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http://dx.doi.org/10.3390/diagnostics10121078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764247PMC
December 2020

Apert Syndrome with Preaxial Polydactyly with FGFR2 Gene Mutation.

Indian J Pediatr 2020 06 26;87(6):469-470. Epub 2019 Dec 26.

Department of Radiology, SMS Medical College and Associated Hospital, Jaipur, Rajasthan, India.

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http://dx.doi.org/10.1007/s12098-019-03140-xDOI Listing
June 2020

Differences and overlaps between Phd studies in diagnostic microbiology in industrial and academic settings.

Med Microbiol Immunol 2020 Jun 29;209(3):217-223. Epub 2019 Nov 29.

Clinical Unit, Biomérieux, 3 Route de Port Michaud, 38390, La Balme Les Grottes, France.

Industrial and academic needs for innovation and fundamental research are essential and not widely different. Depending on the industrial setting, research and development (R&D) activities may be more focused on the developmental aspects given the need to ultimately sell useful products. However, one of the biggest differences between academic and industrial R&D will usually be the funding model applied and the priority setting between innovative research and product development. Generalizing, companies usually opt for development using customer- and consumer-derived funds whereas university research is driven by open innovation, mostly funded by taxpayer's money. Obviously, both approaches require scientific rigor and quality, dedication and perseverance and obtaining a PhD degree can be achieved in both settings. The formal differences between the two settings need to be realized and students should make an educated choice prior to the start of PhD-level research activities. Intrinsic differences in scientific approaches between the two categories of employers are not often discussed in great detail. We will here document our experience in this field and provide insights into the need for purely fundamental research, industrial R&D and current mixed models at the level of European funding of research. The field of diagnostics in clinical bacteriology and infectious diseases will serve as a source of reference.
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http://dx.doi.org/10.1007/s00430-019-00643-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248035PMC
June 2020

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Genomic Evolution of During Artificial and Natural Colonization of the Human Nose.

Front Microbiol 2019 5;10:1525. Epub 2019 Jul 5.

Data Analytics Unit, bioMérieux, La Balme-les-Grottes, France.

can colonize the human vestibulum nasi for many years. It is unknown whether and, how adapts to this ecological niche during colonization. We determined the short (1 and 3 months) and mid-term (36 months) genomic evolution of in natural carriers and artificially colonized volunteers. Eighty-five strains were collected from 6 natural carriers during 3 years and 6 artificially colonized volunteers during 1 month. Multi-locus sequence typing (MLST) and single nucleotide polymorphism (SNP) analysis based on whole-genome sequencing (WGS) were carried out. Mutation frequencies within resident bacterial populations over time were quantified using core genome SNP counts (comparing groups of genomes) and pairwise SNP divergence assessment (comparing two genomes from strains originating from one host and sharing identical MLST). SNP counts (within 1-3 months) in all naturally colonizing strains varied from 0 to 757 (median 4). These strains showed random and independent patterns of pairwise SNP divergence (0 to 44 SNPs, median 7). When the different core genome SNP counts over a period of 3 years were considered, the median SNP count was 4 (range 0-26). Host-specific pairwise SNP divergence for the same period ranged from 9 to 57 SNPs (median 20). During short term artificial colonization the mutation frequency was even lower (0-7 SNPs, median 2) and the pairwise SNP distances were 0 to 5 SNPs (median 2). Quantifying mutation frequencies is important for the longitudinal follow-up of epidemics of infections and outbreak management. Random pattern of pairwise SNP divergence between the strains isolated from single carriers suggested that the WGS of multiple colonies is necessary in this context. Over periods up to 3 years, maximum median core genome SNP counts and SNP divergence for the strains studied were 4 and 20 SNPs or lower. During artificial colonization, where median core genome SNP and pairwise SNP distance scores were 2, there is no early stage selection of different genotypes. Therefore, we suggest an epidemiological cut off value of 20 SNPs as a marker of strain identity during studies on nasal colonization and also outbreaks of infection.
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http://dx.doi.org/10.3389/fmicb.2019.01525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624446PMC
July 2019

Mutational spectrum and identification of five novel mutations in G6PC1 gene from a cohort of Glycogen Storage Disease Type 1a.

Gene 2019 Jun 16;700:7-16. Epub 2019 Mar 16.

Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, India. Electronic address:

Background: Glycogen storage disease type-1a is an inherited, autosomal recessive disorder caused by mutations in G6PC1 gene leading to deficiency of glucose-6-phosphatase-α specifically in the liver/kidney/intestine.

Patients And Methods: DNA of six unrelated Indian GSD-1a patients were screened for mutations in the entire coding region of G6PC1 gene followed by direct DNA sequencing and functional was tested using glucose-6-phosphatase assay.

Results: Mutational screening of GSD-1a patients identified five novel mutations, viz., 1) p.V99Cfs*3, 2) p.G125R, 3) IVS1-2A > T, 4) IVS3 + 39G > A and 5) IVS3 + 42G > A along with three previously reported mutations p.G118D, p.R149Q and p.A331V. Interestingly, each of the p.V99Cfs*3, IVS1-2A > T and p.G118D mutations are identified in two unrelated GSD-1a cases. Further allelic distribution of p.V99Cfs*3 and p.A331V mutations were confirmed by RFLP analysis, consistent with autosomal recessive inheritance. Functional characterization revealed that glucose-6-phosphatase activity was completely abrogated with the mutant proteins p.G125R, p.R149Q, p.G118D, p.A331V and p.V99Cfs*3 than wild-type. However, no significant changes were observed in the expression of mutant constructs at transcription and translation level.

Conclusion: Five novel mutations, p.V99Cfs*3, p.G125R, IVS1-2A > T, IVS3 + 39G > A and IVS3 + 42G > A are reported first time to cause GSD-1a among Indian ethnicity and are not yet reported elsewhere, suggesting separate ethnic founder effects for some mutations among Indian ethnicity.
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http://dx.doi.org/10.1016/j.gene.2019.03.029DOI Listing
June 2019

Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation.

BMC Med Genet 2019 02 14;20(1):31. Epub 2019 Feb 14.

FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, Gujarat, 380015, India.

Background: Gaucher disease is a rare pan-ethnic, lysosomal storage disorder resulting due to beta-Glucosidase (GBA1) gene defect. This leads to the glucocerebrosidase enzyme deficiency and an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. To date, nearly 460 mutations have been described in the GBA1 gene. With the aim to determine mutations spectrum and molecular pathology of Gaucher disease in India, the present study investigated one hundred unrelated patients (age range: 1 day to 31 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality in some of the patients.

Methods: The biochemical investigation for the plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity confirmed the Gaucher disease. The mutations were identified by screening the patients' whole GBA gene coding region using bidirectional Sanger sequencing.

Results: The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all patients. Sanger sequencing established 71 patients with homozygous mutation and 22 patients with compound heterozygous mutation in GBA1 gene. Lack of identification of mutations in three patients suggests the possibility of either large deletion/duplication or deep intronic variations in the GBA1 gene. In four cases, where the proband died due to confirmed Gaucher disease, the parents were found to be a carrier. Overall, the study identified 33 mutations in 100 patients that also covers four missense mutations (p.Ser136Leu, p.Leu279Val, p.Gly383Asp, p.Gly399Arg) not previously reported in Gaucher disease patients. The mutation p.Leu483Pro was identified as the most commonly occurring Gaucher disease mutation in the study (62% patients). The second common mutations identified were p.Arg535Cys (7% patients) and RecNcil (7% patients). Another complex mutation Complex C was identified in a compound heterozygous status (3% patients). The homology modeling of the novel mutations suggested the destabilization of the GBA protein structure due to conformational changes.

Conclusions: The study reports four novel and 29 known mutations identified in the GBA1 gene in one-hundred Gaucher patients. The given study establishes p.Leu483Pro as the most prevalent mutation in the Indian patients with type 1 Gaucher disease that provide new insight into the molecular basis of Gaucher Disease in India.
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http://dx.doi.org/10.1186/s12881-019-0759-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376752PMC
February 2019

Congenital Hydrocephalus, Corpus Callosum Agenesis, and Prosencephalic Cyst with Supernumerary Nostril: A Neurocristopathy.

Asian J Neurosurg 2018 Oct-Dec;13(4):1239-1243

Department of Paediatrics, SMS Medical College, Jaipur, Rajasthan, India.

A 3-month-old-male infant presented with enlargement of head since birth. Clinical and radiological evaluation revealed congenital hydrocephalus, corpus callosum agenesis, prosencephalic cyst, and cranial vault deficiency with supernumerary nostril on the left side. Right ventriculoperitoneal shunt (Chhabra shunt) surgery was performed. The patient did well postoperatively. Parents of the patient have been counseled for repair of supernumerary nostril. Congenital hydrocephalus with corpus callosum agenesis is rare. Furthermore, supernumerary nostril is a very rare anomaly with <40 cases reported in the literature till date. To the best of our knowledge, congenital hydrocephalus, corpus callosum agenesis, prosencephalic cyst, and cranial vault deficiency associated with supernumerary nostril have not been reported till date. We herein briefly review the pertinent literature and describe the embryopathogenesis of this rare association. We propose that this association is a neurocristopathy.
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http://dx.doi.org/10.4103/ajns.AJNS_128_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208241PMC
November 2018

Schmid Type Metaphyseal Chondrodysplasia with a Novel COL10A1 Mutation.

Indian J Pediatr 2019 Feb 12;86(2):183-185. Epub 2018 Sep 12.

Department of Radiology, SMS Medical College and Associated Hospital, Jaipur, Rajasthan, India.

Schmid type metaphyseal chondrodysplasia (SMCD) is a rare skeletal dysplasia, characterized by short stature, short limbs, bowing of the legs, and radiographic features of metaphyseal irregularities with fraying and splaying, more severe at the knee. It is caused by mutations of the COL10A1 gene. The authors present an Indian patient with a novel COL10A1 gene mutation.
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http://dx.doi.org/10.1007/s12098-018-2791-0DOI Listing
February 2019

Cloacal Malformation Variant in a Male Neonate.

J Indian Assoc Pediatr Surg 2018 Apr-Jun;23(2):106-108

Department of Paediatrics, SMS Medical College, Jaipur, Rajasthan, India.

Cloacal malformation is a rare entity and is invariably referred only to females. We are reporting a very rare case of cloacal malformation variant in a 6-day-old male neonate who presented with absent anal opening along with passage of urine and meconium from an abnormal opening in the perineum.
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http://dx.doi.org/10.4103/jiaps.JIAPS_118_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898201PMC
April 2018

Proteus Syndrome with Neurological Manifestations: A Rare Presentation.

J Pediatr Neurosci 2017 Jan-Mar;12(1):109-111

Department of Pediatrics, Sawai Man Singh Medical College, Jaipur, Rajasthan, India.

Proteus syndrome (PS) is an extremely rare and complex disorder. Approximately 200 cases have been reported, and it seems to affect people of all ethnic and racial groups. PS is characterized by segmental overgrowth of multiple tissues and organs including vascular malformations, lipomatous overgrowth, hyperpigmentation, and various types of nevi. We hereby present a 7-year-old boy who presented with seizures and overgrowth of one-half of the body. Although classical physical features have been described, epilepsy and other neurological manifestations are rarely reported features of PS. Early detection of association of epilepsy and hemimegalencephaly with PS can prevent/minimize the neurological complications, disability, morbidity, and mortality.
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http://dx.doi.org/10.4103/jpn.JPN_139_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437773PMC
May 2017

Stickler Syndrome Type 1 with Short Stature and Atypical Ocular Manifestations.

Case Rep Pediatr 2016 28;2016:3198597. Epub 2016 Nov 28.

Department of Paediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan.

Stickler syndrome or hereditary progressive arthroophthalmopathy is a heterogeneous group of collagen tissue disorders, characterized by orofacial features, ophthalmological features (high myopia, vitreoretinal degeneration, retinal detachment, and presenile cataracts), hearing impairment, mild spondyloepiphyseal dysplasia, and/or early onset arthritis. Stickler syndrome type I (ocular form) is caused by mutation in the gene. Ptosis and uveitis are relatively rare ophthalmological manifestations of this syndrome. We report an Indian boy having 2710C>T mutation in gene demonstrating short stature, ptosis, and uveitis with Stickler syndrome.
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http://dx.doi.org/10.1155/2016/3198597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5149639PMC
November 2016

Fetal Valproate Syndrome with Limb Defects: An Indian Case Report.

Case Rep Pediatr 2016 24;2016:3495910. Epub 2016 Nov 24.

Department of Pediatrics, SMS Medical College and Hospitals, Jaipur, Rajasthan, India.

Epilepsy is a common disorder and exposure to antiepileptic drugs during pregnancy increases the risk of teratogenicity. Older AEDs such as valproate and phenobarbital are associated with a higher risk of major malformations in the fetus than newer AEDs like lamotrigine and levetiracetam. Exposure to valproic acid during first trimester can result in fetal valproate syndrome (FVS), comprising typical facial features, developmental delay, and a variety of malformations such as neural tube defects, cardiac and genitourinary malformations, and limb defects. We are presenting an Indian case of FVS with major limb defects.
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http://dx.doi.org/10.1155/2016/3495910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143702PMC
November 2016

The Diagnostic Dilemma of Cutis Laxa: A Report of Two Cases with Genotypic Dissimilarity.

Indian J Dermatol 2015 Sep-Oct;60(5):521

Department of Pediatrics, Division of Genetics and Metabolism, Maulana Azad Medical College, New Delhi, India.

Cutis laxa is a heterogeneous group of diseases, with loose, wrinkled skin folds and hyperelasticity of the skin. There are overlapping of clinical features of the group of syndrome associated with cutis laxa, including congenital cutis laxa, wrinkly skin syndrome and gerodermia osteodysplastica. All these conditions present a challenge to the clinician. Thus, molecular diagnosis is the only way to resolve these phenotypically similar conditions. We hereby describe two Indian patients with wrinkled skin and mild craniofacial dysmorphic features who had molecular confirmation of autosomal recessive cutis laxa.
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http://dx.doi.org/10.4103/0019-5154.164434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601448PMC
November 2015

Identification of a novel MKS locus defined by TMEM107 mutation.

Hum Mol Genet 2015 Sep 29;24(18):5211-8. Epub 2015 Jun 29.

Department of Genetics and Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

Meckel-Gruber syndrome (MKS) is a perinatally lethal disorder characterized by the triad of occipital encephalocele, polydactyly and polycystic kidneys. Typical of other disorders related to defective primary cilium (ciliopathies), MKS is genetically heterogeneous with mutations in a dozen genes to date known to cause the disease. In an ongoing effort to characterize MKS clinically and genetically, we implemented a gene panel and next-generation sequencing approach to identify the causal mutation in 25 MKS families. Of the three families that did not harbor an identifiable causal mutation by this approach, two mapped to a novel disease locus in which whole-exome sequencing revealed the likely causal mutation as a homozygous splicing variant in TMEM107, which we confirm leads to aberrant splicing and nonsense-mediated decay. TMEM107 had been independently identified in two mouse models as a cilia-related protein and mutant mice display typical ciliopathy phenotypes. Our analysis of patient fibroblasts shows marked ciliogenesis defect with an accompanying perturbation of sonic hedgehog signaling, highly concordant with the cellular phenotype in Tmem107 mutants. This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation.
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http://dx.doi.org/10.1093/hmg/ddv242DOI Listing
September 2015

Molar Tooth Sign with Deranged Liver Function Tests: An Indian Case with COACH Syndrome.

Case Rep Pediatr 2015 17;2015:385910. Epub 2015 May 17.

Neurogenetics Laboratory, Department of Neurosciences and Paediatrics, USA ; Rady Children's Hospital, USA ; Howard Hughes Medical Institute, CA, USA.

We report the first genetically proven case of COACH syndrome from the Indian subcontinent in a 6-year-old girl who presented with typical features of Joubert syndrome along with hepatic involvement. Mutation analysis revealed compound heterozygous missense mutation in the known gene TMEM67 (also called MKS3).
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http://dx.doi.org/10.1155/2015/385910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449927PMC
June 2015

Newborn screening for G6PD deficiency: A 2-year data from North India.

Indian J Public Health 2015 Apr-Jun;59(2):145-8

Professor, Department of Paediatrics, Division of Genetics and Metabolism, Maulana Azad Medical College, New Delhi, India.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common erythrocyte enzymopathy, being present in more than 400 million people worldwide that may lead to neonatal jaundice or hemolytic crisis due to drugs or infections. In our study, we aimed to study the frequency of G6PD deficiency in neonates and the proportion of deficient neonates, who developed neonatal hyperbilirubinemia in the study population. The study was an observational one, conducted at the Division of Genetics of Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, over a 2-year period from January 2011 to December 2012. A total of 6,000 newborns delivered during that period underwent newborn screening on 24-72 h of birth. Neonatal hyperbilirubinemia was presented in 13.3% of the study population. Of female neonates, 16% demonstrated G6PD deficiency. This is worth noting for an X-linked recessive trait. Thus, in view of a high gene frequency for a disorder that is manageable with just elimination of few drugs and foodstuff, we stress the need for a newborn screening program for G6PD deficiency.
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http://dx.doi.org/10.4103/0019-557X.157537DOI Listing
May 2015

Adverse pregnancy outcome in patients with low pregnancy-associated plasma protein-A: The Indian Experience.

J Obstet Gynaecol Res 2015 Jul 15;41(7):1003-8. Epub 2015 Mar 15.

Division of Genetics & Metabolism, Department of Pediatrics, Maulana Azad Medical College, New Delhi, India.

Aim: The aim of our study was to examine the association of low pregnancy-associated plasma protein-A (PAPP-A) with adverse pregnancy outcome.

Material And Methods: A total of 1640 consecutive pregnant women between 9(+5) and 13(+6) weeks of pregnancy were recruited. One hundred and thirty women with PAPP-A levels < 0.4 multiple of median were followed till delivery and the outcome information was obtained for fetal loss, birthweight, growth restriction, preterm birth, reduced liquor and development of pre-eclampsia.

Results: During the study period, 130 (7.92%) women had low PAPP-A and were considered as cases and 200 women with normal PAPP-A were controls. Intrauterine growth restriction was observed in 28 (21.54%) cases as compared to 10 (5%) controls. Pre-eclampsia presented in 24 (18.46%) cases and in 18 (9%) controls. Twenty (15.38%) cases had preterm delivery compared to 12 (6%) controls. Fifty-six (43.08%) cases delivered low-birthweight babies compared to 22 (11%) controls. Thus, the incidence of intrauterine growth restriction, preterm birth and low birthweight was significantly more in the cases as compared to the control group.

Conclusions: PAPP-A is a valuable analyte for predicting risk of adverse pregnancy outcome and women with low serum PAPP-A levels would benefit from closer surveillance.
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http://dx.doi.org/10.1111/jog.12662DOI Listing
July 2015

Hypohidrotic ectodermal dysplasia with ankylosis of temporomandibular joint and cleft palate: A rare presentation.

Contemp Clin Dent 2015 Jan-Mar;6(1):110-2

Department of Pediatrics, Division of Genetics and Metabolism, Maulana Azad Medical College, New Delhi, India.

The ectodermal dysplasias are a heterogenous group of diseases, which have one or more anomalies of the hair, teeth, nails, and sweat glands. Hypohidrotic ectodermal dysplasia (HED) is the most common type and is usually transmitted as an X-linked recessive trait. It is characterized by classical triad of hypotrichosis, anhidrosis/hypohidrosis, and hypodontia/anodontia. Here, we describe an Indian boy affected with HED and rare features including ankylosis of temporomandibular joint and cleft palate.
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http://dx.doi.org/10.4103/0976-237X.149304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319327PMC
February 2015

Infantile onset alexander disease with normal head circumference: a genetically proven case report.

J Clin Diagn Res 2014 Nov 20;8(11):PD03-4. Epub 2014 Nov 20.

Professor, Department of Pediatrics, Division of Genetics and Metabolism, Department Of Pediatrics, Maulana Azad Medical College , New Delhi, India .

Alexander disease (AD) is an autosomal dominant leukodystrophy which predominantly affects infants and children. The infantile form comprises the most common form of AD. It presents before two years of age and characterized by macrocephaly, psychomotor regression, spasticity, pyramidal sign, ataxia and seizures. The diagnosis is based on magnetic resonance imaging (MRI) findings and confirmed by Glial fibrillary acidic protein (GFAP) gene molecular testing. We report an Indian case with normal head circumference.
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http://dx.doi.org/10.7860/JCDR/2014/10211.5200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290301PMC
November 2014

Two novel homozygous RAB3GAP1 mutations cause Warburg micro syndrome.

Hum Genome Var 2015 17;2:15034. Epub 2015 Sep 17.

Department of Human Genetics, Yokohama City University Graduate School of Medicine , Yokohama, Japan.

Warburg micro syndrome is an autosomal recessive disease where patients present with optic, neurologic and genital symptoms. Until now, four disease genes for Warburg micro syndrome, RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20, have been identified. Here, we report two novel homozygous RAB3GAP1 mutations (c.22G>T, p.Glu8* and c.1353delA, p.Pro452Hisfs*5) in two consanguineous families by whole-exome sequencing.
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http://dx.doi.org/10.1038/hgv.2015.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785564PMC
April 2016

Molecular diagnosis of infantile Neuro axonal Dystrophy by Next Generation Sequencing.

Indian J Pediatr 2015 May 29;82(5):474-7. Epub 2014 Oct 29.

Division of Genetics & Metabolism, Department of Pediatrics, Maulana Azad Medical College, New Delhi, India.

Infantile Neuro axonal Dystrophy (INAD), is a rare inherited neurological disorder which affects nerve axons causing progressive loss of mental skills, muscular control and vision. The authors present a case of 5.8-y-old girl with INAD who was diagnosed after Next Generation Sequencing (NGS). She was born to a non-consanguineous couple and presented with hypotonia, developmental delay followed by neuroregression and nystagmus after 2 years of age. On examination, bilateral horizontal nystagmus and normal head circumference were noted. Brain MRI showed cerebellar atrophy and altered signal intensities in bilateral globus pallidi and thalami. Magnetic resonance spectroscopy (MRS) showed elevation of lactate. Metabolic testing with Tandem Mass Spectrometry (TMS) and Gas Chromatography Mass Spectrometry (GC-MS) were normal. Mitochondrial disorder was suspected in view of clinical presentation, increased lactate and neuro-imaging suggestive of Leigh syndrome. Mitochondrial Leigh mutations and SURF1 gene sequencing yielded normal results. Lack of a clear diagnosis led to performance of NGS using panel of about 514 genes. A homozygous novel mutation at position c.2277-1G>C in PLA2G6 gene presumed to give rise to altered splicing, was detected, thus confirming the diagnosis of INAD. This report provides evidence of the usefulness of NGS technology as a quick and accurate diagnostic tool for an otherwise complicated genetic disease. To the authors knowledge, this is the first case report with mutations in PLA2G6 gene from India.
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http://dx.doi.org/10.1007/s12098-014-1608-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390426PMC
May 2015

Novel mutation and white matter involvement in an Indian child with pycnodysostosis.

Indian J Pediatr 2015 May 12;82(5):471-3. Epub 2014 Oct 12.

Department of Pediatrics, LHMC and associated Kalawati Saran Children Hospital, New Delhi, India.

Pycnodysostosis (OMIM # 265800) is an inherited lysosomal disorder due to affection of cathepsin K gene, localised to 1q21. Pycnodysostosis can present with both skeletal and extraskeletal features. The index patient presented with cardinal features of short stature, dental and digital anomalies with history of multiple fractures. He, in addition had an unreported finding of white matter hyperintensity suggesting dysmyelination on neuroimaging. Molecular analysis revealed a homozygous insertion of single nucleotide in exon 5 of the CTSK gene that produces the substitution of phenylalanine instead of leucine at position 160 of protein and a premature termination of protein synthesis due to insertion of a stop codon. This mutation (c.480_481insT), (p.L160fsX173) is a novel frameshift mutation. The index case extends the phenotypic spectrum and the list of previously reported mutations in the CTSK gene.
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http://dx.doi.org/10.1007/s12098-014-1582-5DOI Listing
May 2015

Development of dual inhibitors against Alzheimer's disease using fragment-based QSAR and molecular docking.

Biomed Res Int 2014 12;2014:979606. Epub 2014 Jun 12.

School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.

Alzheimer's (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression. β-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BACE-1 and AChE. The GQSAR model provides site-specific clues about the molecules where certain modifications can result in increased biological activity. This information could be of high value for design and development of multifunctional drugs for combating AD.
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http://dx.doi.org/10.1155/2014/979606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075005PMC
September 2015

Hypoglossia-hypodactyly syndrome with short stature - a case report.

J Clin Diagn Res 2014 Apr 15;8(4):SD01-2. Epub 2014 Apr 15.

Professor, Department of Pediatrics, Maulana Azad Medical College Associated Lok Nayak Hospital , New Delhi, India .

The Oromandibular Limb Hypogenesis Syndromes (OLHS) comprises a spectrum of disorders involving the tongue, mandible, and the limbs and are characterized by hypoplastic mandible, absence of the lower incisors, hypoglossia, digits and limbs abnormalities ranges from syndactyly to amelia. In this report, we report a case of OLHS with growth hormone deficiency as a cause of short stature, which has not been described previously to the best of our knowledge.
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http://dx.doi.org/10.7860/JCDR/2014/7809.4281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064859PMC
April 2014

Craniofrontonasal Syndrome: Atrial Septal Defect With a Novel EFNB1 Gene Mutation.

Cleft Palate Craniofac J 2015 Mar 11;52(2):234-6. Epub 2014 Jun 11.

Craniofrontonasal syndrome (CFNS; OMIM # 304110) is a rare X-linked disorder with greater severity in heterozygous females than in hemizygous males. CFNS is characterized by coronal craniosynostosis, frontal bossing, severe hypertelorism, craniofacial asymmetry, downslant palpebral fissure, broad nasal root, bifid nasal tip, grooved fingernails, curly wiry hair, and abnormalities of the thoracic skeleton. There are very few cases describing association of CFNS with heart defects. We discuss a very rare feature: atrial septal defect in a molecularly confirmed case of CFNS.
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http://dx.doi.org/10.1597/13-354DOI Listing
March 2015

Group-based QSAR and molecular dynamics mechanistic analysis revealing the mode of action of novel piperidinone derived protein-protein inhibitors of p53-MDM2.

J Mol Graph Model 2014 Jun 4;51:64-72. Epub 2014 May 4.

School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address:

Tumour suppressor p53 is known to play a central role in prevention of tumour development, DNA repair, senescence and apoptosis which is in normal cells maintained by negative feedback regulator MDM2 (Murine Double Minute 2). In case of dysfunctioning of this regulatory loop, tumour development starts thus resulting in cancerous condition. Inhibition of p53-MDM2 binding would result in activation of the tumour suppressor. In this study, a novel robust fragment-based QSAR model has been developed for piperidinone derived compounds experimentally known to inhibit p53-MDM2 interaction. The QSAR model developed showed satisfactory statistical parameters for the experimentally reported dataset (r(2)=0.9415, q(2)=0.8958, pred_r(2)=0.8894 and F-test=112.7314), thus judging the robustness of the model. Low standard error values (r(2)_se=0.3003, q(2)_se=0.4009 and pred_r(2)_se=0.3315) confirmed the accuracy of the developed model. The regression equation obtained constituted three descriptors (R2-DeltaEpsilonA, R1-RotatableBondCount and R2-SssOCount), two of which had positive contribution while third showed negative correlation. Based on the developed QSAR model, a combinatorial library was generated and activities of the compounds were predicted. These compounds were docked with MDM2 and two top scoring compounds with binding affinities of -10.13 and -9.80kcal/mol were selected. The binding modes of actions of these complexes were analyzed using molecular dynamics simulations. Analysis of the developed fragment-based QSAR model revealed that addition of unsaturated electronegative groups at R2 site and groups with more rotatable bonds at R1 improved the inhibitory activity of these potent lead compounds. The detailed analysis carried out in this study provides a considerable basis for the design and development of novel piperidinone-based lead molecules against cancer and also provides mechanistic insights into their mode of actions.
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http://dx.doi.org/10.1016/j.jmgm.2014.04.015DOI Listing
June 2014

Phenotypic variability in two families of Muenke syndrome with FGFR3 mutation.

Indian J Pediatr 2014 Nov 6;81(11):1230-2. Epub 2014 Apr 6.

Department of Pediatrics, MAMC Associated Lok Nayak Hospital, New Delhi, India.

Muenke syndrome is a nonsyndromic coronal craniosynostosis, characterised by clinical and radiological variability, with occurrence of both familial and sporadic cases. Pro250Arg (P250R) is a pathogenic mutation, causing this highly clinically heterogeneous syndrome reported worldwide irrespective of race and ethnicity. The authors describe three Indian cases in two different families showing phenotypic spectrum of the disease, which was later confirmed by genetic testing.
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http://dx.doi.org/10.1007/s12098-014-1424-5DOI Listing
November 2014