Elucidating the Phenotype and Genotype Spectrum of Junctional Epidermolysis Bullosa in India

posted Feb 21, 2017, 7:52 AM by Vinod Scaria

  • Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogenous group of genetic skin disorders.•
  • We show the utility of WES in understanding the phenotype and genotype spectrum in four Indian JEB families.•
  • Computational modeling studies have been used to understand the probable molecular consequence of a missense mutation on the structure-function relationship of lamininβ3 protein.•
  • This is the first report documenting the phenotype-genotype correlations of JEB patients from India.
Yenamandra VK, Vellarikkal SK, Kumar M, Chowdhury MR, Jayarajan R, Verma A, Scaria V, Sivasubbu S, Ray SB, Dinda AK, Kabra M, Kaur P, Sharma VK, Sethuraman G
Application of Whole Exome Sequencing in Elucidating the Phenotype and Genotype Spectrum of Junctional Epidermolysis Bullosa: A Preliminary Experience of a Tertiary Care Centre in India
J Dermatol Sci (2017) in press.

Egyptian tale from India: application of whole-exome sequencing in diagnosis of atypical familial Mediterranean fever

posted Feb 21, 2017, 7:48 AM by Vinod Scaria

Autoinflammatory diseases encompass a spectrum of diseases characterized by dysfunction of the innate immune system. Until recently, these diseases were largely classified and diagnosed by the clinical presentation. The recent years have seen the delineation of the molecular mechanisms and specific molecular markers for diagnosing these illnesses.A number of autoinflammatory diseases have well established genetic basis and associated variations as described in literature. Several such diseases also have strong geographical preponderance. Diagnosis of these conditions, therefore, requires an intense clinical suspicion and sound molecular evidence, especially in regions where the prevalence is low. In this manuscript, we report a case of atypical familial Mediterranean fever (FMF) in an Asian Indian patient whose ancestry could be traced to Egypt.

Sandhya P, Vellarikkal SK, Nair A, Ravi R, Mathew J, Jayarajan R, Kumar A, Verma A, Sivadas A, Danda D, Sivasubbu S*, Scaria V*
Egyptian tale from India - application of whole-exome sequencing in diagnosis of atypical Familial Mediterranean Fever
Int J Rheum Dis (2017) DOI: 10.1111/1756-185X.13042

Rescue of neural crest derived phenotypes in a zebrafish CHARGE model by sox10 downregulation

posted Jul 21, 2016, 4:44 AM by Vinod Scaria   [ updated Jul 21, 2016, 4:47 AM ]

CHD7 mutations are implicated in a majority of cases of the congenital disorder, CHARGE syndrome. CHARGE, an autosomal dominant syndrome, is known to affect multiple tissues including eye, heart, ear, craniofacial nerves and skeleton and genital organs. Using a morpholino-antisense-oligonucleotide-based zebrafish model for CHARGE syndrome, we uncover a complex spectrum of abnormalities in the neural crest and the crest-derived cell types. We report for the first time, defects in myelinating Schwann cells, enteric neurons and pigment cells in a CHARGE model. We also observe defects in specification of peripheral neurons and craniofacial skeleton as previously reported. Chd7 morphants have impaired migration of neural crest cells and deregulation of sox10 expression from the early stages. Knocking down sox10 in the zebrafish CHARGE model rescued the defects in Schwann cells and craniofacial cartilage. Our zebrafish CHARGE model thus reveals important regulatory roles for Chd7 at multiple points of neural crest development viz., migration, fate choice and differentiation and we suggest that sox10 deregulation is an important driver of the neural crest-derived aspects of chd7 dependent CHARGE syndrome.

Asad Z, Pandey A, Babu A, Sun Y, Shevade K, Kapoor S, Ullah I, Ranjan S, Scaria V, Bajpai R, Sachidanandan C.
Hum Mol Genet. 2016 Jul 13. pii: ddw198. [Epub ahead of print]

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If you are a Clinician and you think your patients would benefit from our Science, please join our collaborative effort GUaRDIAN, one of the largest clinical research networks for research in India working on Rare Genetic Diseases. 

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Case Report: Whole exome sequencing reveals a novel frameshift deletion mutation p.G2254fs in COL7A1 associated with autosomal recessive dystrophic epidermolysis bullosa

posted Jun 19, 2016, 5:36 AM by Vinod Scaria   [ updated Jun 27, 2016, 2:32 AM ]

Dystrophic epidermolysis bullosa simplex (DEB) is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB) is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES). Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India.

F1000Research 2016, 5:900 (doi: 10.12688/f1000research.8380.1)

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mit-o-matic: a comprehensive computational pipeline for clinical evaluation of mitochondrial variations from next-generation sequencing datasets

posted Jan 24, 2016, 4:19 AM by Vinod Scaria   [ updated Jun 19, 2016, 5:32 AM ]

The human mitochondrial genome has been reported to have a very high mutation rate as compared with the nuclear genome. A large number of mitochondrial mutations show significant phenotypic association and are involved in a broad spectrum of diseases. In recent years, there has been a remarkable progress in the understanding of mitochondrial genetics. The availability of next-generation sequencing (NGS) technologies have not only reduced sequencing cost by orders of magnitude but has also provided us good quality mitochondrial genome sequences with high coverage, thereby enabling decoding of a number of human mitochondrial diseases. In this study, we report a computational and experimental pipeline to decipher the human mitochondrial DNA variations and examine them for their clinical correlation. As a proof of principle, we also present a clinical study of a patient with Leigh disease and confirmed maternal inheritance of the causative allele. The pipeline is made available as a user-friendly online tool to annotate variants and find haplogroup, disease association, and heteroplasmic sites. The "mit-o-matic" computational pipeline represents a comprehensive cloud-based tool for clinical evaluation of mitochondrial genomic variations from NGS datasets. The tool is freely available at 

Human Mutation. 2015 Apr;36(4):419-24.

Whole exome sequencing helps in accurate molecular diagnosis in siblings with a rare co-occurrence of paternally inherited 22q12 duplication and autosomal recessive non-syndromic ichthyosis

posted Aug 25, 2015, 12:32 AM by Vinod Scaria   [ updated Jun 19, 2016, 5:37 AM ]

Lamellar ichthyosis (LI), considered an autosomal recessive monogenic genodermatosis, has an incidence of approximately 1 in 250,000. Usually associated with mutations in the transglutaminase gene (TGM1), mutations in six other genes have, less frequently, been shown to be causative. Two siblings, born in a collodion membrane, presented with fish like scales all over the body. Karyotyping revealed duplication of the chromosome arm on 22q12+ in the father and two siblings. Whole exome sequencing revealed a homozygous p.Gly218Ser variation in TGM1; a variation reported earlier in an isolated Finnish population in association with autosomal recessive non-syndromic ichthyosis. This concurrence of a potentially benign 22q12+ duplication and LI, both rare individually, is reported here likely for the first time.

Gupta A, Sharma Y, Deo K et al. 
Case Report: Whole exome sequencing helps in accurate molecular diagnosis in siblings with a rare co-occurrence of paternally inherited 22q12 duplication and autosomal recessive non-syndromic ichthyosis. 
F1000Research 2015, 4:446 (doi:10.12688/f1000research.6779.1)

Whole-exome sequencing solves diagnostic dilemma in a rare case of sporadic acrokeratosis verruciformis

posted Jan 18, 2015, 10:05 PM by Vinod Scaria   [ updated Jun 19, 2016, 7:41 AM ]

In the present report, we explore the application of next-generation sequencing approach to quickly identify the causative mutation in a sporadic case of a rare dermatological disease. We suggest that exome sequencing could be an alternative to traditional gene sequencing approach to quickly identify the variations and be able to make an appropriate diagnosis in clinical settings.


Gupta A, Sharma YK, Vellarikkal SK, Jayarajan R, Dixit V , Verma A ,Sivasubbu S and Scaria V*
Whole-exome sequencing solves diagnostic dilemma in a rare case of sporadic acrokeratosis verruciformis
Journal of the European Academy of Dermatology and Venereology (2015) Accepted

Exome sequencing reveals a novel mutation, p.L325H, in the KRT5 gene associated with autosomal dominant Epidermolysis Bullosa Simplex Koebner type in a large family from western India

posted Nov 1, 2014, 12:19 AM by Vinod Scaria   [ updated Jun 19, 2016, 7:42 AM ]

Shamsudheen K Vellarikkal, Ashok Patowary, Meghna Singh, Renu Kumari, Mohammed Faruq, Dilip C Master, Sridhar Sivasubbu& Vinod Scaria

We report a large, non-consanguineous family comprising five generations of individuals residing in Gujarat, India affected with localized Epidermolysis Bullosa Simplex (EBS) Koebner type. We analyzed 14 individuals including 9 affected individuals from this family. Exome sequencing in two cases suggested a novel non-synonymous variation, p.L325H, in the KRT5 gene. The present analysis also reports the first causative mutation of EBS Koebner type from India.

Vellarikkal SK, Patowary A, Singh M, Kumari R, Faruq M, Master DC, Sivasubbu S*and Scaria V*

Systematic Pharmacogenomis analysis of a Malay whole genome: Proof of concept for personalized medicine

posted Jul 3, 2013, 11:59 PM by Vinod Scaria   [ updated Jun 19, 2016, 7:42 AM ]

Salleh MZ*, Teh LK, Lee LS, Ismet RI, Patowary A, Joshi K, Pasha A, Ahmed AZ, Janor MH, Hamzah AS, Adam I, Yusoff K, Hoh BP, Hatta FM, Ismail MI, Scaria V*, Sivasubbu S*

PLoS ONE (2013) Accepted

Background: With a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realization of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine.

Methods: Genomic DNA was obtained from a 55 years old, self-declared healthy, anonymous male of Malay descent was sequenced. The subject’s mother died of lung cancer and the father had a history of schizophrenia and deceased at the age of 65 years old. A systematic, intuitive computational workflow/pipeline integrating custom algorithm in tandem with large datasets of variant annotations and gene functions for genetic variations with pharmacogenomics impact was developed. A comprehensive pathway map of drug transport, metabolism and action was used as a template to map non-synonymous variations with potential functional consequences.
Principle findings: Over 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetics analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolizing enzyme genes and 33 target genes harboring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings.

Conclusions: The current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes. These will be essential for realizing personalized medicine through the use of comprehensive computational pipeline for systematic data mining and analysis.

Keywords: Human Genome Re-sequencing, Pharmacogenomics, Malaysian, Personal Genome, Analysis Pipeline

Systematic analysis and functional annotation of variations in the genome of an Indian individual.

posted Jul 1, 2013, 7:35 AM by Vinod Scaria   [ updated Jul 1, 2013, 7:37 AM ]

Patowary A, Purkanti R, Singh M, Chauhan RK, Bhartiya D, Dwivedi OP, Chauhan G, Bharadwaj D, Sivasubbu S, Scaria V.
Hum Mutation. 2012 Jul;33(7):1133-40. doi: 10.1002/humu.22091. Epub 2012 Apr 16.

Whole genome sequencing of personal genomes has revealed a large repertoire of genomic variations and has provided a rich template for identification of common and rare variants in genomes in addition to understanding the genetic basis of diseases. The widespread application of personal genome sequencing in clinical settings for predictive and preventive medicine has been limited due to the lack of comprehensive computational analysis pipelines. We have used next-generation sequencing technology to sequence the whole genome of a self-declared healthy male of Indian origin. We have generated around 28X of the reference human genome with over 99% coverage. Analysis revealed over 3 million single nucleotide variations and about 490,000 small insertion-deletion events including several novel variants. Using this dataset as a template, we designed a comprehensive computational analysis pipeline for the systematic analysis and annotation of functionally relevant variants in the genome. This study follows a systematic and intuitive data analysis workflow to annotate genome variations and its potential functional effects. Moreover, we integrate predictive analysis of pharmacogenomic traits with emphasis on drugs for which pharmacogenomic testing has been recommended. This study thus provides the template for genome-scale analysis of personal genomes for personalized medicine.

Variation Data at the Asian Genome Browser [Asian Genome Browser]

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