Dear All,

Greetings from a sunny East Anglia.

In this update:

- DECIPHER v11.11 Released

o New cardiac features

§ Case/control cohort data

§ Hot spot regions (PM1)

o ACMG secondary finding genes

o Recommendations for reporting of cancer susceptibility genes

o Links to Transcript Archive

o GenCC classification colouring for ClinGen and G2P gene/disease associations

- Planned Update to Inheritance Terms

- Inactive DECIPHER Accounts

- Wellcome Funding and Move to EBI

DECIPHER v11.11 Released 

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You can also view this on the web at: https://www.deciphergenomics.org/about/news

DECIPHER now displays case/control cohort information for cardiac disease genes to demonstrate the confidence of the gene-phenotype relationships where these cohorts are available. Case/control cohort data can be viewed for MYH7 in relation to dilated cardiomyopathy and hypertrophic cardiomyopathy here: https://www.deciphergenomics.org/gene/MYH7/overview/clinical-info

For genes associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and Long-QT syndrome, we now show regions considered to be mutational hot spots or critical domains on the protein browser. This will make it easier to know when to apply the ACMG PM1 criterion during a variant pathogenicity assessment. The regions are annotated for the disease and the strength of evidence recommended. The following link shown the PM1 domain for MHY7 associated with hypertrophic cardiomyopathy: https://www.deciphergenomics.org/gene/MYH7/overview/protein-genomic-info

Where the ACMG recommend reporting secondary findings, we have added this information to the clinical tab on gene pages, patient variant gene tabs and genes tables. Secondary finding information for RB1 can be viewed here under the Management resources section here: https://www.deciphergenomics.org/gene/RB1/overview/clinical-info

Recommendations for reporting of cancer susceptibility genes as published in Talukdar et al., 2019 (https://europepmc.org/article/MED/31018999) are now included in the description of DECIPHER CNV syndromes on the Overview tab, where those syndromes involve a cancer susceptibility gene. This information can be seen for Familial Adenomatous Polyposis here: https://www.deciphergenomics.org/syndrome/49/overview

Links to Transcript Archive (TARK, https://tark.ensembl.org) are now provided if a user attempts to deposit a variant using an old transcript version. TARK provides interfaces to allow users to visualise the differences between transcript versions. The following TARK page allows the comparison of NM_001101 ACTB transcripts: https://tark.ensembl.org/web/transcript_details/NM_001101.4/

In addition, the strengths of gene-disease relationships asserted by ClinGen and G2P on gene tabs now match the colours used for those classifications by GenCC, (whose data sources include ClinGen and G2P). This can be viewed for FGFR1 here: https://www.deciphergenomics.org/gene/FGFR1/overview/clinical-info

Planned Updated to Inheritance Terms

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In May we plan to remove the “de_novo” inheritance option and start supporting the inheritance options “de novo (parentage confirmed)” and “de novo (unconfirmed parentage)”. This will allow depositors to record confirmed parental relationships versus assumed parental relationships status for de novo variants, which is important when determining the strength given to case level data during a variant pathogenicity assessment.

We plan to update all deposited “de novo” variants to “de novo (unconfirmed parentage)”, unless we know that parentage has been confirmed (e.g. when the project contains trio exome data, in these cases will be updated to “de novo (parentage confirmed)”).

If the de novo variants from your centre should be updated to “de novo (parentage confirmed)”, rather than “de novo (unconfirmed parentage)”, please email contact@deciphergenomics.org and provide details.

Inactive DECIPHER Accounts

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It is important that DECIPHER accounts are linked only to individuals who are currently actively working in research or clinical genetics.

We will soon be identifying and locking a number of DECIPHER accounts which no longer appear to be in use to minimise the risk of unauthorised access. If you last logged into DECIPHER prior to 17th June 2020, please make sure you log in again using your email address and password, if you want to retain your access to DECIPHER. After 17th June 2022, we intend to lock accounts which have not been accessed in the previous two years. If your account is locked, you will need to reset your password before you can regain access.

We're very grateful for the coordinators who monitor their project's lists on an ongoing basis.

Wellcome Funding and Move to EBI

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DECIPHER has been awarded a new Wellcome grant to continue its work through to 2025. Key goals include better support for variants in the non-coding genome, helping users find relevant functional evidence, and building models to link genes and disorders with phenotypes. The grant will allow us to keep DECIPHER up to date with best practice and emerging opportunities in clinical interpretation as the landscape evolves.

The grant also provides for a transition of DECIPHER’s hosting and development from the Wellcome Sanger Institute (where DECIPHER began and has been based for the last 18 years) to the European Bioinformatics Institute (EMBL-EBI; https://www.ebi.ac.uk), which runs Ensembl and its Variant Effect Predictor (VEP), Gene2Phenotype and many other resources which are critical to DECIPHER’s work. Co-PI Helen Firth will remain the clinical lead; Matt Hurles will step back as co-PI but will remain involved as a collaborator and Fiona Cunningham, who leads EBI’s Genome Interpretation Team, will join as co-PI. Both institutes are committed to a smooth transition and the migration will not involve any changes to the address (URL), the appearance, or the functionality of DECIPHER.

The Deciphering Developmental Disorders (DDD) project (https://www.ddduk.org), which has recruited nearly 14,000 families in the UK and Ireland, will still deliver results through DECIPHER, while the research work will remain at Sanger.

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We look forward to your feedback and suggestions for improvement. Please use the "Feedback" button which is available on every page and fill in the simple form to get in touch with us. Your details will be filled in automatically if you are logged in.

Best Regards

Julia, on behalf of the DECIPHER team

Julia Foreman PhD

DECIPHER Project Manager

Email: contact@deciphergenomics.org

Web: https://www.deciphergenomics.org

Twitter: @decipher_wtsi

Julia Foreman PhD

DECIPHER Project Manager

Wellcome Sanger Institute

Hinxton

Cambridge CB10 1SA

Tel: 01223-492392

E-mail: jf11@sanger.ac.uk

https://www.deciphergenomics.org

Please note, I work on Monday and Tuesday mornings, all day Wednesday, Thursday and Friday