Sequence Variant Literature Search Tips and Tricks - PowerPoint Presentation

Slide1

Sequence Variant Literature Search Tips and Tricks

Jessica Mester, MS, LCGC

Disclosure

I am an employee of GeneDx, Inc., a wholly-owned subsidiary of OPKO Health, Inc.

Overview

Effective use of variant nomenclature in your lit searchWhere to look?Common lit search speed bumps and how to overcome them

Purpose of the literature search

Find articles that allow for application of ACMG criteria during variant curationFunctional studies

Case reports (

de novo

, segregation, phenotype, co-occurrence)

Molecular characterization

Case-control data

Evidence might be for or against pathogenicity

Better understand phenotypic spectrum

There is not one perfect literature search tool

– combination of sources might be necessary!

Starting your search

HGMD (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php

)

Professional ($$$) version

Public (free) version – 3 years behind, available to academic/non-profit users

Gene-specific databases

Several listed at

https://grenada.lumc.nl/LSDB_list/lsdbs

(Locus Specific Database List), maintained by LOVD

If you are focusing on one gene/disease, and it has a dedicated variant database, become best friends with that resource!

ClinVar: some submitters provide citations, not all specific to variant

Make sure to review the article yourself to ensure your specific variant is actually present!

Literature Search Tools

MasterMind: https://mastermind.genomenon.com

/

Others in development

Google/GoogleScholar

> PubMed

PubMed: may “hit” if variant in abstract or title, but that’s it!

Google

Helpful: locates variants in article text, supplemental tables

Not as helpful: also finds non-genetics related links (ATM variants: finds you ATM machines at an address resembling your variant nomenclature)

Detective work sometimes needed to figure out what article a table is from

GoogleScholar

Limited to published academic literature

Better than regular google at finding variants in tables within a paper

Building Google Search Terms

GENE AND (“V1” OR “V2” OR “V3”….)

Take a “generous” approach to nomenclature – authors might not use strict HGVS format!

Include genomic position (GRCh37/hg19 still most used)

Remember alternate or “historic” gene names (STK11 = LKB1, NBN = NBS1…)

Know if

alternate transcripts

or nomenclature used in addition to HGVS (standard)

MUTYH: alternate transcripts (c.1187G>A/p.G396D = c.1145G>A/p.G382D)

BRCA1/2: BIC nomenclature; nucleotide numbering starts at the beginning of the cDNA clone.

Watch for “push to the right”

Finding Alternate Transcripts/Nomenclature

Might be on a laboratory report

In the VCI: appears in “basic information” of Evidence View; also on

ClinVar

variant page

Excellent

article on this subject

: PMID

30096381

, DiStefano M et al.

J

Mol

Diagn

. 2018 Nov;20(6):789-801. “Curating Clinically Relevant Transcripts for the Interpretation of Sequence Variants

.” (Companion talk by Dr. DiStefano on

ClinGen

YouTube channel)

“Push to the Right” examples

Normal sequence: CTGCTGCTGAAAAAVariant deletion of one “A”: CTGCTGCTG

A

AAAA

Could be named c.25delA OR c.29delA – can’t tell

which

A is really deleted.

HGVS nomenclature would “push to the right” – c.29delA

Deletion 3 base pairs in repetitive sequence: CT

GCT

GCTGAAAAANo matter which three are deleted, surrounding sequence reads the same

CT

GCT

GCTGAAAAA CTGCT

GCT

GAAAAA

CTG

CTGCTGAAAAA

Consider alternate potential nomenclatures accordingly

15

21

25

29

Lit Search Term Examples

Variant

Type

Lit

search string

Nonsense

PTEN AND (“1003C>T” OR “1003 C>T” OR “Arg335Ter” OR “R335X” OR “Arg335STOP” OR “89720852”)

Missense

NF1 AND (“277T>C” OR “277 T>C” OR “Cys93Arg” OR “C93R” OR “29486100”)

Frameshift

MYBPC3

AND (“1028delC” OR “1028del” OR “Thr343MetfsX7” OR “T343MfsX7” OR “Thr343Metfs*” OR “T343Mfs*” OR “47367820”)

Intronic

FBN1

AND (“1148-2A>C” OR “1148-2 A>C” OR “IVS10-2A>C” OR “IVS10-2 A>C” OR “48808561”)

In-frame

indel

MSH6 AND ("2157_2159delTAC" OR "2157delTAC" OR "2157del3" OR "Thr720del" OR "T720del“ OR “48027279”)

Different amino

acid change at same residue

Variant

of interest: TP53 His179Asn

TP53 AND (“His179*” OR “H179*”) – would

NOT

include “NOT His179Asn” because one article might discuss both variants.

* = wildcard operator; finds anything starting with what precedes it.

Google Search Results

Don’t worry, it’s not that badSeveral links: take you to websites that have extracted variants or info from

ClinVar

,

gnomAD

, other databases

Can pull up articles where MYBPC3 mentioned, but variant with same nomenclature found in a different gene

Over time: becomes easier to recognize potentially useful hits

Finding Source Publications for Google “Hits”

Best case scenario: link takes you directly to article.

Database “Hits”

ClinVar

: typically top of search results

LOVD entry

Detective Work Needed

Clues: name of document indicates first or last author likely to be BH

Funke

, published in Genetics in Medicine during 2010, “200661” might be article number

Journal website…

Google Scholar

Caution: double-dipping

Same individual/family may be reported in several different articlesOccasionally recognized and previous publications cited

If not, look for…

Overlapping authors

Patient recruitment/ascertainment in article methods

Helpful clinical details (gender, ethnicity, family history…)

If it’s a rare variant, and several of these factors line up…most likely to be the same individual

In Summary

Finding helpful literature is a learning process, skills honed with time and experienceUse available database resources to help increase efficiency

Use comprehensive nomenclature terms in Google and

GoogleScholar

searches

Always verify that your specific variant of interest is included in a publication

Thank You!

ClinGen Education Working Group

Karen Wain

Danielle

Azzaritti

Sarah Barnett

Lisa Kurtz

Erin Riggs

PTEN VCEP Biocurators

Felicia Hernandez

Melody Perpich

Kaitlin Sesock

Other

ClinGen

/Broad folks

Jenny Goldstein

Steven Harrison

Becky

Siegert

www.clinicalgenome.org

clingen@clinicalgenome.org

ClinGen

is primarily funded through NHGRI through the following three grants:

U41HG006834, U41HG009649,

U41HG009650.