Checking the expertsCompliance with author instructions regarding HGVS nomenclature and database submission

6th Human Variome Project meeting, June 2, 2016

Zgjim Osmani, student-assistant Generadetaschner@generade.nl

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IntroductionAim: Improving quality of genetic variant & phenotype descriptions

Author instructions:

HGVS nomenclature Yes/No?

Database submission Yes/No?

January 2016 issues of genetics journals

Sharing reliable information for diagnostic use

Genetic testing in Amsterdam: 178 nationalitiesMigration challenges DNA diagnostics

Problem:Different populationshave different variants:effects unknown,characterized as VUS

Solution:World-wide data sharing

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Material & Methods

Human Variome Project’s Journal List

Check the variant flowchart

HGVS nomenclature: Mutalyzer Name Checker tool

Extra attention: Reference sequences & RNA analysis

Students of the University of Applied Sciences Leiden

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Material & Methods DNA – Day

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Variant terminology Reference sequences

Total of 126 articlesRelevant: 59 articles

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12% contains incorrect DNA variant descriptions

RNA descriptionsreported for 1% of variants only

31% of variantssubmitted to databases

Variant descriptions summaryNumber of articles: 59

8Leiden Muscular Dystrophy pages (www.DMD.nl) Johan den Dunnen

c.636C>T r.(636c>u) p.(=) Prediction:Coding synonymous

Muscular Dystrophy PatientDatabase provides information about variant effects

9Leiden Muscular Dystrophy pages (www.DMD.nl) Johan den Dunnen

Muscular Dystrophy PatientDatabase provides information about variant effects

c.636C>T r.535_652del p.Asp179Valfs*23

RNA analysis:Different effect than predicted!

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Review and database curation is important!Variant in article:

NM_002778.2(PSAP_v001): c.777_778ins24 (no RNA description) p.Met259_Gln260ins8

Cesani et al. (2016), Mutation update of ARSA and PSAP genes causing Metachromatic Leukodystrophy, Human Mutation, 16 – 27.

Variant in database:

Exon boundary: NG_009301.1(PSAP_v001): c.777_777+1ins… ?NG_009301.1(PSAP_v001): c.778-1_778ins… ?

Insertion of 33 nucleotidesUnchecked Mutalyzer Position Converter result?

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• Genomic reference sequences frequently omitted

• RNA descriptions not mentioned

• Reviewers & editors could help to improve quality:Reject manuscripts not following the authors instructions

Conclusions

Jeroen F. J. LarosKoen van DiemenJulia. A Lopez Hernandez

DNA day Hackathon Team: Floyd Wittink Samuel van Apeldoorn Sabine BlekerWessel BomJasper BoomMark uit het BroekDavy Cats

Leonie Didden

Jolanda EssensHendrik FreieGuido GrootIlke van den HoekMarten HoogeveenMidia KhalifaLisa KnijnenburgMelanie KooijAnnemijn Manger

Thomas OlivierAaricia van Oostrom

Kevin van RooijenLieke Schoenmaker, Matthias Tammes BuirsOlga VethTim SmithRozemarijn van der Vooren

Acknowledgments

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Results

Human Mutation January ‘16Total Articles Total

VariantsNM_Refse

q Protein Predictions Using the word "Mutation"

14 192 8 of 9 162 8 of 9Genomic and

Genetic Articles Checked

Novel Variant

NG_Refseq

HGVS Protein Predictions

Using the word "Variant"

9 61 0 of 9 156 (96%) 8 of 9

New individuals

HGVS Variants NP_Refseq RNA Change

ManuscriptUsing the word "Polymorphism

"70 186 (97%) 1 of 9 1 4 of 9

Phenotype Submission

Variant Submission NC_Refseq RNA Change

Database43 (61%) 63 (33%) 1 of 9 30

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American Journal of Human Genetics January ‘16

Total Articles Total Variants

NM_Refseq Protein Predictions Using the word

"Mutation"16 52 5 of 5 29 5 of 5

Genomic and Genetic Articles Checked

Novel Variant

NG_Refseq

HGVS Protein Predictions

Using the word "Variant"

5 36 0 of 5 28 (97%) 5 of 5

New individuals

HGVS Variants NP_Refseq RNA Change

ManuscriptUsing the word "Polymorphism

"72 51 (98%) 1 of 5 0 2 of 5

Phenotype Submission

Variant Submission NC_Refseq RNA Change

Database45 (63%) 34 (65%) 0 of 5 0

Results

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ResultsEuropean Journal of Human Genetics

January ‘16Total Articles Total

VariantsNM_Refse

q Protein Predictions Using the word "Mutation"

26 103 8 of 8 96 4 of 8Genomic and

Genetic Articles Checked

Novel Variant

NG_Refseq

HGVS Protein Predictions

Using the word "Variant"

8 42 2 of 8 96 (100%) 8 of 8

New individuals

HGVS Variants NP_Refseq RNA Change

ManuscriptUsing the word "Polymorphism

"215 103

(100%) 4 of 8 6 3 of 8

Phenotype Submission

Variant Submission NC_Refseq RNA Change

Database132 (61%) 93 (90%) 1 of 8 76