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2016 Annual Minutes 0 W. Ouwehand ISTH-SSC 2016 Meeting Montpellier May 25-28 SSC Genomics in Thrombosis and Hemostasis (SSC GinTH) Minutes  Room Rondelet, Friday 27th May 2016, 14:15-18:45,   Chairman: Professor Willem H Ouwehand (United Kingdom) Co-Chairs: Dr Daniel Bellissimo (United States) - absent Professor Paul Bray (United States) - absent Professor Kathleen Freson (Belgium) - present Professor Anne Goodeve (United Kingdom) - present Dr Michele P Lambert (United States) - present   Presentations   Speaker: Jose Maria Bastida (Spain). Title: Design and Application of a twenty-three-gene panel by NGS for inherited coagulation bleeding disorder. The results of the panel test were presented based on a national initiative across Spain with many examples of multiple cases per rare disease type.  It illustrated how national collaboration in the field of Next Gen Seq can quickly deliver benefits for patients and their close relatives.   Session 1 Moderator: Professor Willem H Ouwehand (United Kingdom)   Welcome by Professor Willem H Ouwehand Professor Willem H Ouwehand presented an overview of the SSC Genomics in Thrombosis and Haemostasis.   Title: ThromboGenomics High Throughput Sequencing Platform. Speaker: Kate Downes (Cambridge, UK) Question about coverage – >costs of sequencing become less important – MDT members time is more costly Question about Sanger confirmation -> Willem Ouwehand pointed out that this is likely to become more redundant/cost inefficient and likely that after the ISTH Conference in Berlin (2017) we decide not to do it anymore for simple variants.  More complex variants may require confirmation by Sanger sequencing. Question  - new genes do they cause specific diseases – [3 of these just say thrombo/macrothrombocytopenica] -> Kathleen Freson pointed out these were multi-tissue disorders – e.g. DIAPH1 gain-of-function resulting in macrothrombocytopenia and deafness Question  – Transcription Factor genes (e.g. RUNX1, ETV6, etc) and the increased risk of cancer – there needs to be clear policy on difference between research and routine clinical service -> the Odds Ratio (OR) needs to be more precisely defined -> calculating OR values is only possible if we aggregate cases across countries -> decisions on introduction of ‘predictive testing’ need to consider national policies and guidelines -> the principle of ‘autonomy’ should be a key driver in setting policies - several people argued that our obligation as professionals is to provide ‘information in an objective and evidence based manner’ and inform the public about the pro’s and con’s of genetic tests -> the principle of autonomy needs to replace the ‘paternalistic’ approach of ‘doctor knows best’   Title: Statistical challenges of identifying the genetic determinant of rare diseases. Speaker: Ernest Turro  (UK) Question: How do we tell whether variants in the non-coding space are disease causing? –> The statistical principals for identifying putative causal rare variants were reviewed Comment: phenotypes may change over time (e.g. in MYH9-related disorders) and it is therefore important to capture changes in phenotype with progressing age -> New statistical methods are required to use the data richness (OMIM, MPO, HPO, etc) to assign likelihoods to genes and variants therein of being causal of rare disease    Session 2 Moderator: Andres Greinacher (Germany)   Title: Assigning pathogenicity status to DNA variants Speaker: Kathleen Freson (Belgium) Kathleen Fresson reported on the European and US guidelines for reporting variants: -          “variant” is the word to use, not “mutations” or “polymorphisms” -          VUS must not be included in clinical reports, -          VUS can be included in research report to draw the attention of clinician-scientists to certain variants which require further study (e.g. co-segregation, functional genomics studies, etc.  -          conservative reporting on the status of variants as ‘likely pathogenic variant’ and ‘pathogenic variant’ (LPV and PV, respectively) should be the mantra Question: Policy paper on variant/mutation/polymorphisms Willem H Ouwehand (WHO): -          The American Society for Hematology (ASH) has started a Precision Medicine task force providing a forum to set policies on high-penetrance germline variants and somatic mutations; policies and guidelines will be developed over the next 24 months with short manuscripts in Blood. -          There will be an informal discussion at the EHA-Copenhagen meeting on having a similar cross-cutting Scientific Working Group for the EHA   Title: Reference Variant Databases Speaker: Karyn Mégy (UK) and Muriel Giansily-Blaizot (France) Presentations dealt with the need for consistence use of a frame of reference for the consistent annotation of variants; Databases like LRG, ClinVar and EAHAD were reviewed and a in-depth review of F7 variants and their clinical consequences. Question: What about variants in other loci that modify the severity of phenotype; identifying such modifiers requires large datasets on thousands of patients? The application of genome-wide typing in combination with HTS panel tests may provide an approach to identify ‘strong modifiers’ in the future.    Session 3 Moderator: Andreas Greinacher (Germany)   Title: Regulation of haemostasis by miRNAs: implication for thrombus formation Speaker: Martinez Gomez (Spain) This talk provided a comprehensive and authoritative overview over the role of miRNA’s in platelet biology.  Question: Are there examples of rare inherited platelet diseases which are caused by variants in the miRNA genes or miRNA binding sites -> Dicer knockout in mice does alter platelet proteomics   Title: Differential diagnosis of congenital macrothrombocytopenia Speaker: Shinji Kunishima (Japan) The presentation reviewed the current state of knowledge on macrothrombocytopenia with a focus on ACTN1 Title: Reprogramming of platelet miRNA induced by activation Speaker: Giovanni Cimmino (Italy) Question – How long after activation do you see difference in mRNA expression -> time course up to 2 hour Question –do miRNAs influence thrombus formation? -> possibly miRNAs act early in activation   Session 4 Moderator: Kathleen Freson (Belgium)   Title: Common gene variation affecting platelet function Speaker: Leonard Edelstein (United States) Leonard gave an excellent talk about genome wide association studies for platelet function and the role of expression-QTLs at GWAS associated regions as the underlying mechanism.  Several eQTL datasets have now been produced and it would be interesting to investigate the possibility of merging data to create a ‘truth set’ Question – about ethnicity è Could it be that admixture may have explained the observed associations between variants and platelet function è Ethnicity was being included in the analysis using the genome-wide types to cluster cases of different ethnicity.   Title: Phenotyping and genotyping of inherited platelet disorders: experience from a Spanish National Project. Speaker: Jose Rivera Pozo (Spain) Questions – how many Glanzmann cases have been identified? -> tens of cases and most cases have their own causal variants   General discussion Anne Goodeve (UK) advertised a workshop: ISTH Advanced Training Course in Thrombosis and Haemostatis. Location: St Anne’s College, Oxford, England, UK. Dates: Sept. 6th -9th, 2016.   Kate Downes proposed to include four new genes to the Tier 1 list: -          CHST14 -          DIAPH1 -          MECOM (previously EVI1) -          TUBB1  This was accepted by the membership   Karyn Mégy advised that: (1)   LPV and PV should be submitted to the ClinVar database (2)   Tier 1 genes and the clinically relevant transcript(s) must be registered with the Locus Reference Genomics database. (3)   Richer annotation of variants has been achieved through Locus Specific Databases, e.g. EAHAD for F7, F8, F9 and VWF, Glanzmann Thrombasthenia, …..   Andreas Greinacher did bring up the issue of rare variants in transcription factor genes implicated in bleeding and platelet disorders that may enhance the risk of malignancies (e.g. RUNX1, ETV6, WAS).   Comments from SSC membership: -          This needs to be a debate for the public. In the UK this is starting to happen….. and is widely supported by the media -          We should respect the principle of autonomy; we need to inform patients and their close relatives and offer choice -          If a patient consent to a genetic test they need to be informed upfront that they may receive results about increased risks for malignancies, deafness, kidney insufficiency, etc.   Panel discussion: sharing genotype and phenotype data in inherited disorders. WHO  Introduction of a Green Paper about adopting a practice of sharing of data on genotype and phenotype.  Fort Lauderdale Agreement[1]: make sequence data available as early as possible. o   Genome sequence data generated across Europe are submitted to the European Genome-phenome Archive (EGA) The Green Paper discussion document will be distributed to the SSC membership using the services provided by the SSC office The membership of the SSC is to be consulted on the content of the Green Paper with the aim to develop a White Paper for ratification at the ISTH meeting Berlin 2017 The White Paper would inform the working of the ISTH-SSC for Genomics in Thrombosis and Haemostasis (SSC-GinTH)   Actions Attendees to the meeting should register as Member of the SSC-GinTH at Green Paper will be circulated via ISTH-SSC website   Andreas Greinacher: Sharing OK, but at which time point, which type of data? Between data and publishing paper can take 2 years … share straight away, or when abstract submitted, or when paper accepted?   WHO:  in UK we have 6-months (100 000 Genomes Project) or 12-months timeline (NIHR BioResource – Rare Diseases, Deciphering Developmental Disorders project) for genotype and phenotype data release; these timelines are contractually stipulated by the fund providers. Sharing data early should be the mantra, but everyone recognises that ‘researchers need their manuscripts to enhance their chances for future funding   Publications   WHO: Instead of publishing manuscripts reporting on a couple of patients by several groups, we may want to consider to have manuscripts with many cases per gene (see Green Paper) About half of the audience agreed with that, the rest had no opinion or was not that much in favour of early data sharing It was pointed out that those that were not in support of data sharing may not be attending the meeting   Writing committee for genes   Maha Othman: writing committee: who does what, who’s authoring etc. Is it a fixed formula? Is that decided by the writing committee for a certain paper?   Self-organisation of the Writing Committee but WHO suggested that they should:  1. multi-disciplinary 2. include early career researchers 3. small committee membership (cannot write a paper with 25 people) 4. requirement for experts in bioinformatics and statistical genomics   The following manuscripts which would make use of the ThromboGenomics HTS results were discussed:   Rémi Favier has offered to lead on the writing of a manuscript about ~35 Grey Platelet Syndrome (GPS) cases – anyone who wants to include GPS cases should contact Remi Favier at or Tadbir Bariana at   Paolo Gresele has expressed an interest to lead on the writing about the aggregated MYH9 cases – those who want to contribute should contact Prof Paolo Gresele at   Andreas Greinacher – there is a study on the use of manganese in MYH9 patients. Anyone who can contribute cases please contact Andreas Greinacher at We do not want multiple underpowered observational studies – so let’s join forces in the interest of patients   WHO: Offered to collate all new LPV and PVs in the Tier 1 genes (see Green Paper), and do a single upload to ClinVar once a year on behalf of the SSC-GinTH (see Green Paper). Interested parties are to contact Karyn Megy at   There was wide support for the above proposed manuscripts and attendees who want to contribute to a Writing Committee should email the lead author.   What about intellectual property   WHO: The vast majority of research on Rare Diseases is pre-competitive in nature. The Supreme Court of America has ruled that the relation between germline variants and phenotype cannot be patented   European Genome-phenome Archive (EGA)[2] WHO introduced EGA: Sequences and variants and phenotypes information can be submitted to the EGA – access is regulated by a Data Access Committee (i.e. SSC Chair and Co-Chairs would oversee access to data until publication). Question: Kathleen Freson Sequences are available via EGA, but how much phenotype is given? WHO: phenotype, detailed enough to be useful, but not too much that would allowed to identify the patient, e.g. higher level leaves of HPO tree. The equivalent in the US is dbGaP[3]. dbGaP and EGA exchange metadata information, not sequence files. The presentations are available as pdf files at the following link:   Willem H Ouwehand, Cambridge, UK June 2016 [1] Fort Lauderdale Report:   [2] EGA: [3] dbGAP
by W. Ouwehand
Tuesday, June 28, 2016
2015 Annual Minutes 0 L. Schmeidler Chairman: Willem Ouwehand Co-Chairs: Paul F. Bray, Kathleen Freson, Anne Goodeve, Michele P. Lambert, Pieter Reitsma Part 1: NGS IN DIAGNOSTICS 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: Development and validation of a NGS test for rare inherited T & H disorders Identification and annotation of pertinent genes and variation in these genes to clinical standards Development and maintenance of a database to provide a stable and sustainable frame of reference for sequence information 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.   Part 2: NGS IN DIAGNOSTICS 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.   EDUCATIONAL SESSION 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.   REPORTING OF CLINICAL VARIANTS 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 Progress 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. 
by L. Schmeidler
Thursday, July 9, 2015
2014 Annual Minutes 0 W. Ouwehand Working Group on Genomics in Hemostasis  Chairmen: Anne Goodeve (UK, excused), Willem H Ouwehand (UK), Pieter Reitsma (the Netherlands) Monday, 23 June (14:15-18:15)  Session 1 – Chair – Willem H Ouwehand, Cambridge, UK Professor Willem H Ouwehand opened the session thanking all the people attending the ThromboGenomics Working Group on Genomics.    Speaker: Professor Kathleen Freson – Belgium Title: Human Phenotype Ontology Terms: Does it works? The underlying principles and the use of Human Phenotype Ontology (HPO) terms for phenotype clustering in patients with bleeding and platelet disorders was outlined. A key difference between HPO and other bleeding phenotype ontologies is the ability to also code pathobiologies outside the narrow remit of bleeding and platelet disorders. It is hoped that this will provide additional power in gene discovery programmes.    Speaker: Dr Anne Kelly – UK Title: Application of HPO to bleeding and platelet disorders The HPO coding allows standardised recording of detailed clinical phenotype. A logic clustering code was developed and applied to 716 HPO-coded cases with bleeding and platelet disorders. Some preliminary evidence was presented that the automated clustering of cases may facilitate gene discovery    Speaker: Dr Daniel Hampshire – UK Title: The coagulation factor variant database An update on the combined European CoagDB portal to provide access to variant databases for all coagulation factors. There has been excellent progress with the F8 database and it is hoped that efforts on F7 and F11 will be completed by Dec 2014            Speaker: Dr Daniel Bellissimo – USA Title: The role of the curator for the ThromboGenomics database One of the aims of the ThromboGenomics project is to develop a sustainable and high quality curated database of gene annotations including clinically relevant DNA sequence variants for rare inherited bleeding and platelet disorders (BPD). The importance of a stable reference sequence, of gene annotation at Locus Reference Genomic (LRG), and the curator’s responsibilities of the interpretation of sequence variants have been discussed.  Integration of BPD gene sequence variants with these of other control databases (1000 Genomes, NHLBI-ESP, UK10K, GEL100K, etc.) is seen as a critical development in cleaning up historical erroneous data entries.    Session 2 - Chair: Pieter Reitsma, Leiden, the Netherlands    Speaker: Dr Ji Wu – USA Title: Discover with Confidence: NimbleGen Target Enrichment Technology for next generation sequencing The NimbleGen target enrichment protocol and design, in use for the ThromboGenomics samples, have been presented.     Speaker: Dr Ilenia Simeoni – UK Title: A NGS Diagnostic Platform for inherited bleeding and platelet disorders An update on the three main activities of the ThromboGenomics project: 1) Development of a next generation sequencing (NGS) platform 2) gene curation and 3) database development for stable references of sequence variations were presented.  Good progress has been made on all three activities and it is expected that the validation of the NGS platform will have been completed by June 2015.     Speaker: Professor Willem H Ouwehand in substitution of Dr Augusto Rendon – UK Title: Genomic medicine in the care path of patients with bleeding and platelet disorders Discussed the advances of genomic medicine to discover new genes and new variants to elucidate the mechanism of unresolved bleeding and platelet disorders.Whole genome sequencing is now available at low cost and provides better coverage than whole exome sequencing in the coding ("exome”) space. The importance of data sharing has also been highlighted    Speaker: Dr Jill Johnsen – USA Title: NGS approaches in familial ITP Results of a whole exome sequencing study on two pedigrees with familial ITP were presented. No conclusive results could be drawn and further cases will require analysis to identify the genetic architecture of this rare disorder.                       Speaker: Dr Pieter Reitsma – The Netherlands Title: Resequencing of 100 cases with Familial Thrombophilia Results of the targeted resequencing of 100 cases with familial thrombophilia were presented. Final Remarks     Progress The ThromboGenomics (TG) project is now in the final stage of the validation of the next generation sequencing platform. Significant improvements have been achieved for the establishment of a stable database where sequence variations can be stored. The global TG network continues to expand including new collaborators, curators, clinicians and researchers from all around the world. Similarly exciting advances have been made with the European CoagDB portal and as both databases are "open access” there seems to be a great opportunity to fuse the knowledge of these two databases.  It was generally accepted that the largest challenge was the accurate curation of variant databases.    New chairman Willem H Ouwehand mentioned at the opening and closing of the meeting that the Genomics Working Group requires at least one new Chairman.  One of the two founder Chairman of ThromboGenomics Dr Thomas Kunicki (USA) has stood down from his post because of retirement.  It was emphasised that since the other three Chairs are from Europe that it was essential to have representation from other continents.  Members and attendees of ISTH with an interest to be appointed to one of the two vacant posts were invited to submit their CV before Friday 11th July by email to Dr Ilenia Simeoni at or Prof Willem H Ouwehand at     Transition to SSC SubcommitteeWillem H Ouwehand attended the ISTH SSC meeting and was informed that ThromboGenomics could apply for SSC subcommittee status.   A relatively "light” application process is to be followed to achieve this possible transition.    Dr Ilenia Simeoni PhD Scientific Coordinator ThromboGenomics Cambridge Translational Genomics Laboratory Cambridge, UK July 2014.  Website: 
by W. Ouwehand
Thursday, June 19, 2014
2013 Annual Minutes 0 W. Ouwehand Working Group on Genomics in Hemostasis Chairman: Anne Goodeve (UK)Chairman: Thomas J. Kunicki (USA)Chairman: Willem H. Ouwehand (UK)Chairman: Pieter Reitsma (Netherlands) June 29, 2013Minutes will be posted following the meeting.
by W. Ouwehand
Wednesday, June 19, 2013
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