Leveraging the power of Genomics in Precision Medicine

ClinGenics Ltd is a UK company founded in late 2016, with the aim of advancing patient care and support through the development and provision of state-of-the art clinical decision-support and genomic testing solutions for physicians and patients

Overcoming the bottleneck and the challenges
of variant interpretation

The biggest single hurdle today in terms of clinical applications of NGS is
how to translate NGS data into clinically actionable results

Background

As genome or exome sequencing of an individual typically generates thousands of gene variants relative to the human reference sequence, identifying the variant(s) of potential causative effect, i.e. clinically significant variant(s) directly related to the patient’s phenotype, is a challenging and demanding task.

In order to address these challenges, and starting in early 2012, the first version of the Exome Management Application-EMA® pipeline software was designed and implemented. For more than 5 years the Exome Management Application-EMA® pipeline has been methodically developed, refined and field-tested in more than 600 whole exome sequencing (WES) clinical cases, to become a very powerful variant interpretation tool, aiding decisively in the diagnosis of hundreds of complex and rare disorders (see publications).

The final variant interpretation report provided by ClinGenics has the added important feature of incorporating expert manual curation, personalized interpretation and case-specific comments and suggestions for further actions, thus fulfilling its role as a true decision support tool.

Team – Scientific Advisors

Christopher Konialis, MSc, PhD

Founder – Director, Chief Scientific Officer

Chris obtained an MSc degree in Biochemistry and a PhD degree in Molecular Genetics from University College London and was subsequently employed at UCL as a post-doctoral research fellow. His work abroad was interrupted in 1985 in order to return to Greece for his army service and he remained in the country, employed as a Research Associate-Group Leader in the Center for Biological Research of the Hellenic Research Foundation, as head of a research group studying gene expression of the human erythropoietic system. In the last 15 years he heads The Department of Molecular Genetics and Genomics at InterGenetics SA-Diagnostic Genetics Centre, Athens, Greece. Overall, has more than 30 years of experience in molecular genetics and clinical molecular genetics and genomics, having developed many breakthrough applications. Is a member of numerous international scientific societies, has published several first-author original papers in international journals and he actively participates as a speaker in national and international meetings and congresses in the field of medical genetics and genomics.
In close collaboration with Zach Agioutantis, over the last 5 years they developed the Exome Management Application-EMA® pipeline software, a cutting-edge bioinformatics pipeline for variant prioritization and clinical interpretation of NGS data.

Prof. Zach Agioutantis

Scientific Advisor - IT

Zach is Mining Engineering Foundation Professor, Department of Mining Engineering, Univ. of Kentucky, and holds MSc and PhD degrees from the Department of Mining and Minerals Engineering, Virginia Polytechnic Institute and State University.
Among many other notable accomplishments, he has been successful in developing the first Windows-based suite of computer programs to calculate and predict surface deformations (SDPS) due to underground coal mines and this package has been constantly updated and is now the official package used by the US Office of Surface Mining Reclamation and Enforcement (OSMRE) for subsidence calculations. In recent years, he also developed cutting-edge relational database applications for the management of large real-time data sets broadcasted by OPC servers, allowing the data to be automatically processed and displayed for changes and annotation.
Since 2012, in close collaboration with Chris Konialis, Zach has been instrumental in developing the Exome Management Application-EMA® pipeline software as a big-data, multi-user, client/server relational database application that combines offline and online genome/exome variant information and data processing.

Christopher Konialis, MSc, PhD

Founder – Director, Chief Scientific Officer

Chris obtained an MSc degree in Biochemistry and a PhD degree in Molecular Genetics from University College London and was subsequently employed at UCL as a post-doctoral research fellow. His work abroad was interrupted in 1985 in order to return to Greece for his army service and he remained in the country, employed as a Research Associate-Group Leader in the Center for Biological Research of the Hellenic Research Foundation, as head of a research group studying gene expression of the human erythropoietic system. In the last 15 years he heads The Department of Molecular Genetics and Genomics at InterGenetics SA-Diagnostic Genetics Centre, Athens, Greece. Overall, has more than 30 years of experience in molecular genetics and clinical molecular genetics and genomics, having developed many breakthrough applications. Is a member of numerous international scientific societies, has published several first-author original papers in international journals and he actively participates as a speaker in national and international meetings and congresses in the field of medical genetics and genomics.
In close collaboration with Zach Agioutantis, over the last 5 years they developed the Exome Management Application-EMA® pipeline software, a cutting-edge bioinformatics pipeline for variant prioritization and clinical interpretation of NGS data.

Prof. Zach Agioutantis

Scientific Advisor - IT

Zach is Mining Engineering Foundation Professor, Department of Mining Engineering, Univ. of Kentucky, and holds MSc and PhD degrees from the Department of Mining and Minerals Engineering, Virginia Polytechnic Institute and State University.
Among many other notable accomplishments, he has been successful in developing the first Windows-based suite of computer programs to calculate and predict surface deformations (SDPS) due to underground coal mines and this package has been constantly updated and is now the official package used by the US Office of Surface Mining Reclamation and Enforcement (OSMRE) for subsidence calculations. In recent years, he also developed cutting-edge relational database applications for the management of large real-time data sets broadcasted by OPC servers, allowing the data to be automatically processed and displayed for changes and annotation.
Since 2012, in close collaboration with Chris Konialis, Zach has been instrumental in developing the Exome Management Application-EMA® pipeline software as a big-data, multi-user, client/server relational database application that combines offline and online genome/exome variant information and data processing.

Apostolos “Paul” Psychogios, MD, FACMGG

Ex-officio Clinical Consultant - Global Medical Affairs

Dr. Paul is a medical graduate of the University of Athens, Greece (1989). He completed his residency in Cardiology at Onassis Cardiac Surgery Center, Greece (1998), Medical Genetics at Columbia University (2005), and his fellowship in Clinical Molecular Genetics at Harvard University (2006). He is a Diplomate of the American Board and a Fellow of the American College of Medical Genetics and Genomics. Over the last 12 years, he has held practicing privileges and academic appointments at various institutions including Mayo Clinic, Vanderbilt University and Cleveland Clinic. He is currently an Associate Professor of Pediatrics and Medicine at the University of Kentucky where he is also the head of the Cardiovascular Genetics and Precision Medicine Program at the UK Gill Heart & Vascular Institute. He has particular and extensive experience in the diagnosis and management of cardiogenetic disorders (cardiomyopathies, cardiac arrhythmias), cardiovascular and connective tissue disorders (Marfan syndrome, Ehlers-Danlos syndrome, thoracic aneurysms) and also in the management of patients with pediatric and adult syndromes, birth defects, developmental disorders, autism, neurogenetic disorders and cancer. He is particularly interested in the application of genomics in the prevention of disease and best-informed care across the life span.

Birgitta Hagnefelt, MSc

Scientific Advisor - NGS applications

Birgitta received an MSc degree in Biochemistry from the University of Lund, Sweden. She spent 2 years as a Research Assistant in the Dept. of Tumor Immunology, Wallenberg Laboratory, University of Lund and then joined the Center for Biological Research of the Hellenic Research Foundation in Athens, Greece, as a Research Assistant, where for 10 years she worked in the Chemical Carcinogenesis Group and subsequently in the Eucaryotic Molecular Genetics Group. In the last 15 years she is a senior staff member in The Department of Molecular Genetics at InterGenetics-Diagnostic Genetics Centre, with particular involvement in NGS and PGD clinical applications and has published original papers in numerous international journals.

Konstantinos G. Lilakos

Scientific Advisor - NGS Support

Kostas obtained a BSc degree in Biology and is currently a PhD candidate (under thesis defense review) in the field of Molecular Hematology. He has several years work experience as Research Assistant in a variety of research projects related to Molecular Hematology and in the last 10 years he is active as Department Head and Coordinator of Service and Support and also Senior Application Support Scientist-NGS with AntiSel SA. His expertise includes development of NGS methodologies for the negotiation of familial cases of lymphoid malignancies, development of targeted resequencing panels for investigation of multiple myeloma cases, installation, deployment and customer support of NGS platforms, development of diverse NGS applications, being also proficient in several bioinformatics and IT applications, such as GATK toolbox, deployment, customization and support of Linux, *NIX environments and R-package applications.

Katerina Vrotsou, PhD

Scientific Advisor - IT

Katerina is currently Assistant Professor, Department of Science and Technology (ITN) and Media and Information Technology (MIT), Linköping University, Sweden. She received her MSc degree in Media Technology and Engineering and her PhD degree in Visualization and Interaction from Linköping University. Her current work revolves mainly in the field of interactive visual analysis of multi-dimensional event-based data and her research interests include information visualization, visual analytics, data mining and interactive knowledge discovery.

More Info

Variant interpretation

  1. Amendola LM, Jarvik GP, Leo MC, et al Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet. 2016;98:1067-1076.
  2. Ackerman JP, Bartos DC, Kapplinger JD, et al The promise and peril of precision medicine: phenotyping still matters most. Mayo Clin. Proc. 2016;91:1606-1616.
  3. Eilbeck K, Quinlan A, Yandell M. Settling the score: variant prioritization and Mendelian disease. Nat Rev Genet. 2017;18:599-612.
  4. MacArthur DG, Manolio TA, Dimmock DP, et al Guidelines for investigating causality of sequence variants in human disease. Nature 2014;508:469-76.
  5. Richards S, Aziz N, Bale S, et al Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.
  6. Thiffault I, Bernard G. Expert opinion and caution are imperative for interpretation of next generation sequencing data. Eur J Med Genet. 2016;59:519-21.
  7. Thiffault I, Lantos J. The Challenge of Analyzing the Results of Next-Generation Sequencing in Children. Pediatrics 2016;137 Suppl 1:S3-7.

 

General info

  1. Bamshad MJ, Ng SB, Bigham AW, et al Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 2011;12:745-755.
  2. Harrison SM, Riggs ER, Maglott DR et al Using ClinVar as a resource to support variant interpretation. Curr. Protoc. Hum. Genet. 2016;89; 8.16.1-8.16.23.
  3. Jian X, Boerwinkle E, Liu X. In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res. 2014;42:13534-44.
  4. Karczewski KJ, Weisburd B, Thomas B, et al The ExAC browser: displaying reference data information from over 60,000 exomes. Nucleic Acids Res. 2017;45(D1):D840-D845.
  5. Kircher M, Witten DM, Jain P, et al A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 2014;46:310-315.
  6. Köhler S, Vasilevsky NA, Engelstad M, et al The Human Phenotype Ontology in 2017. Nucleic Acids Res. 2017;45:D865-D876.
  7. Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44:D862-D868.
  8. Lek M, Karczewski KJ, Minikel EV, et al Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536:285–291.
  9. Liu X, Jian X, Boerwinkle E. dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat. 2011;32:894-9.
  10. Rehm HL, Berg JS, Brooks LD, et al ClinGen-the Clinical Genome Resource. N. Engl. J. Med. 2015;372:2235-2242.
  11. The 1000 Genomes Project Consortium, Auton A, Brooks LD et al A global reference for human genetic variation. Nature 2015;526:68-74.

 

Publications

  1. Konialis C, Hagnefelt B, Karapanou S, Pangalos C. Whole exome sequencing in a newborn with severe distal arthrogryposis reveals homozygosity for a paternal ECEL1 gene mutation as a result of uniparental paternal isodisomy for chromosome 2 (manuscript in preparation)
  2. Konialis C, Lilakos K, Hagnefelt B, Karapanou S, Pangalos C. A Microdeletion at Xp11.22 Detected by Whole Exome Sequencing Confirms SHROOM4 Association with Stocco dos Santos Syndrome and XLID in a Large Kindred (manuscript submitted)
  3. Gontika M, Konialis C, Pangalos C, Papavasiliou A. Novel SCN1A and GABRA1 gene mutations with diverse phenotypic features and the question on the existence of a broader spectrum of Dravet Syndrome Child Neurol Open. 2017 May 8;4:2329048X17706794
  4. Konialis C, Asimakopoulos E, Hagnefelt B, Karapanou S, Sotiriadis A, Pangalos C. Prenatal diagnosis of X-linked Myopathy associated with a VMA21 gene mutation afforded through a novel targeted exome sequencing strategy applied in fetuses with abnormal ultrasound findings. Clin Case Rep 2017;5:308–311.
  5. Pangalos C, Hagnefelt H, Lilakos K, Konialis C. First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects. Peer J 2016 Apr 26;4:e1955.

 

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