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2015 Annual Minutes
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7/9/2015 at 1:49:53 PM GMT
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2015 Annual Minutes

Chairman: Willem Ouwehand

Co-Chairs: Paul F. BrayKathleen FresonAnne GoodeveMichele P. LambertPieter Reitsma


Moderators: Professor Willem H Ouwehand (United Kingdom) and Dr Michele P Lambert (United States)


Welcome by Professor Willem H Ouwehand

Professor Willem H Ouwehand presented an overview of the SSC Genomics in Thrombosis and Haemostasis.

Key people involved in the project and key activities have been presented.

Activities include:

  1. Development and validation of a NGS test for rare inherited T & H disorders
  2. Identification and annotation of pertinent genes and variation in these genes to clinical standards
  3. Development and maintenance of a database to provide a stable and sustainable frame of reference for sequence information
  4. Development and application of Human Phenotype Ontology terms (HPO) to patients


Speaker: Dr Char Witmer – Philadelphia, USA

Title: Inherited bleeding /coagulation disorder

Dr Witmer has presented the limitations to coagulation testing to diagnose patients with bleeding and coagulation disorders. She talked about some of the current applications of genetic testing for VWF and Haemophilia A and B underlying the limitations of the available tests including the high costs and the importance of having a new comprehensive test such as a NGS platform with higher sensitivity and specificity.


Speaker: Professor Anne Goodeve – Sheffield, UK

Title: Hemostasis NGS panel in routine diagnostic use

The NGS gene panel currently available at Sheffield Diagnostic Genetics Service to screen patients with bleeding and platelet disorders has been presented. Sample workflow and GATK bioinformatics pipeline currently in use have been described including the way variants are filtered according to frequency and pathogenicity to identify the potential causative variant.

The platform has been validated with control samples and performance assessed, and has been in diagnostic service use for 6 months for sample from the UK and worldwide. Availability of several genes on the panel facilitates discrimination between disorders where necessary; e.g. haemophilia A and B, haemophilia A and type 2N VWD and also provides more rapid analysis for disorders resulting from more than one gene e.g. FIX deficiency, Glanzmann thrombasthenia and fibrinogen disorders.


Speaker: Dr Ilenia Simeoni, Cambridge, UK

Title: ThromboGenomics platform

An update about the ThromboGenomics (TG) project has been presented. The TG platform is now fully validated and will become a NGS platform for routine clinical use from July 2015. A single, comprehensive DNA based test will be offered to all the UK Haemophilia Centres to screen patients with bleeding, thrombotic and platelet disorders. The gene panel includes so far 86 genes and in the validation phase about 400 samples have been enrolled, sequenced and analysed. Results are discussed in MDT meetings and reports generated for the referring clinicians using Sapientia, a new software developed by Congenica Ltd.



Moderators: Professor Anne Goodeve (United Kingdom) and Dr Walter Kahr (Canada)

Speaker: Dr Dan Hampshire – Sheffield, UK

Title: Coagulation Factor Variant Databases - an update

An update about the EAHAD-DB (European Association for Haemophilia and Allied Disorders Coagulation Factor Variant Databases) initiative has been presented. The intention of this initiative is to gather together single gene variant databases involved in clinical bleeding disorders, principally haemophilias A and B and von Willebrand disease, as well as other rarer coagulation factor variants. So far F7, F8, F9 and VWF databases have been included. In future, databases for fibrinogen and factors FII, FV, FX, FXI and FXIII will also be included. The database is free, easily accessible and open to any new variant submission, including submission of previous reported variants.


Speaker: Dr Andrew Paterson, Toronto, Canada

Title: Challenges in the interpretation of variants from next generation sequencing

Many false positive variants are present in current databases. NGS and the availability of whole exome and whole genome sequencing (WES and WGS, respectively) on a large number of controls will help to remove several of the misinterpreted variants in addition to the identification of new variants likely to cause an inherited disease. Advantages and limitations of the Exome Aggregation Consortium (ExAC) variant database have also been mentioned.



Moderators: Professor Pieter H Reitsma (The Netherlands) and Professor Paul Bray (United States)

Speaker: Dr Ernest Turro Cambridge, UK

Title: Methodological challenges of gene discovery by genome sequencing

An overview about sequencing strategies, variant calling and filtering of sequencing data has been presented. One of the challenges of WGS is variant prioritization. The process includes multiple steps and takes advantage of the use of the Human Phenotype Ontology (HPO) terms, pathogenicity score and a novel statistical methodology call “phenotype similarity regression”. WGS enables detection of variations also in the non-coding regions of the genome adding a further level of complexity to the bioinformatics analysis.


Speaker: Dr Walter Kahr, Toronto, Canada

Title: Inherited platelet disorders

An overview about inherited bleeding disorders and their classification have been presented. Glanzmann Thrombasthenia, Bernard Soulier, Hermansky Pudlak and Arthrogryposis - Renal dysfunction – Cholestasis (ARC) syndromes have been presented in details. The recent discovery of germline mutations in ETV6 as a cause of autosomal dominant thrombocytopenia, red cell macrocytosis and ALL was also presented.



Moderators: Professor Kathleen Freson (Belgium) and Dr Daniel Bellissimo (United States)

Speakers: Dr Daniel Bellissimo, Pittsburgh, USA  & Professor Kathleen Freson, Leuven, Belgium

Title: International Guidelines to annotate pathogenic variants

This was a joint presentation between Dr Dan Bellissimo, who was the first speaker, and Professor Kathleen Freson.

The first presentation described the recently published ACMGG/AMP Guidelines for the interpretation of sequence variant in US (Richards et al (2015 Genet in Med 17(5): 405-423).

This guideline for interpretation of sequence variants is an evidence-based scoring system that considers the strength of the following pieces of evidence when classifying variants as pathogenic, likely pathogenic, uncertain significance, likely benign and benign:

  • Population Data
  • Computational and Predictive Data
  • Functional Data
  • Segregation Data
  • De novo Data
  • Allelic Data
  • Other Database
  • Other Data

The second talk was about the Guidelines for the Interpretation of sequence variants in Europe.

NGS not only influences diagnostic outcome but also the complete organization of genome care that can no longer be the sole responsibility of clinical geneticists but of Multi Disciplinary Team (MDT) that includes research specialists, clinicians, bioinformaticians and clinical geneticists.

Conclusions include the importance of variant databases, wide data sharing within and between countries, the importance of a careful re-classification of variants of unknown significance (VUS) and MDT for variant interpretation and reporting.

Speakers: Dr Karyn Megy, Cambridge, UK & Dan Hamshire, Sheffield, UK

Title: New large control data: opportunities & pitfalls

The outline of this joint talk included an update about the current variation databases (dbSNP, dbVar, ClinVar, Human Gene Mutation Database (HGMD) and Locus specific databases (LSBDs)) and the large volume of datasets coming from WES and WGS. Opportunities and pitfalls of the available large datasets were presented. Opportunities of having large datasets to help in classifying a variant include availability of controls, phenotypes and ethnicity data but there are pitfalls to consider: false positive variants present in public databases, the type of sequencing which might not be sufficient to identify the causal variant and a lack of standardisation for variant description, the reference sequence and phenotype coding.

To avoid these pitfalls, the use of multiple datasets, a standardisation of the variant description in addition to the use of a stable database such as Locus Reference Genomic (LRG) which includes a unique stable sequence record of transcripts using IDs and no versioning.


Final Remarks


The ThromboGenomics (TG) project, which was informally initiated by Kunicki and Ouwehand at the ISTH in Kyoto (2011) is now after extensive validation moving to the clinical stage. The global TG network continues to expand to include new collaborators, clinicians and researchers from all around the world. 

Last edited Tuesday, August 18, 2015
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