Top

Published in:

Open Access 01-12-2014 | Research article

A systematic approach to the reporting of medically relevant findings from whole genome sequencing

Authors: Heather M McLaughlin, Ozge Ceyhan-Birsoy, Kurt D Christensen, Isaac S Kohane, Joel Krier, William J Lane, Denise Lautenbach, Matthew S Lebo, Kalotina Machini, Calum A MacRae, Danielle R Azzariti, Michael F Murray, Christine E Seidman, Jason L Vassy, Robert C Green, Heidi L Rehm, for The MedSeq Project

Published in: BMC Medical Genetics | Issue 1/2014

Abstract

Background

The MedSeq Project is a randomized clinical trial developing approaches to assess the impact of integrating genome sequencing into clinical medicine. To facilitate the return of results of potential medical relevance to physicians and patients participating in the MedSeq Project, we sought to develop a reporting approach for the effective communication of such findings.

Methods

Genome sequencing was performed on the Illumina HiSeq platform. Variants were filtered, interpreted, and validated according to methods developed by the Laboratory for Molecular Medicine and consistent with current professional guidelines. The GeneInsight software suite, which is integrated with the Partners HealthCare electronic health record, was used for variant curation, report drafting, and delivery.

Results

We developed a concise 5–6 page Genome Report (GR) featuring a single-page summary of results of potential medical relevance with additional pages containing structured variant, gene, and disease information along with supporting evidence for reported variants and brief descriptions of associated diseases and clinical implications. The GR is formatted to provide a succinct summary of genomic findings, enabling physicians to take appropriate steps for disease diagnosis, prevention, and management in their patients.

Conclusions

Our experience highlights important considerations for the reporting of results of potential medical relevance and provides a framework for interpretation and reporting practices in clinical genome sequencing.

Available only for authorised users

Green RC, Rehm HL, Kohane IS: Clinical genome sequencing. Genomic and Personalized Medicine. Edited by: Ginsburg GS, Willard HF. 2013, Academic Press, Oxford

Biesecker LG, Green RC: Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014, 370: 2418-2425. 10.1056/NEJMra1312543.CrossRefPubMed

Dixon-Salazar TJ, Silhavy JL, Udpa N, Schroth J, Bielas S, Schaffer AE, Olvera J, Bafna V, Zaki MS, Abdel-Salam GH, Mansour LA, Selim L, Abdel-Hadi S, Marzouki N, Ben-Omran T, Al-Saana NA, Sonmez FM, Celep F, Azam M, Hill KJ, Collazo A, Fenstermaker AG, Novarino G, Akizu N, Garimella KC, Sougnez C, Russ C, Gabriel SB, Gleeson JG: Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med. 2012, 4: 138ra178-10.1126/scitranslmed.3003544.CrossRef

Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, Dimaruo S, Thorburn DR, Mootha VK: Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012, 4: 118ra110-10.1126/scitranslmed.3003310.CrossRef

Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, Meisler MH, Goldstein DB: Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012, 49: 353-361. 10.1136/jmedgenet-2012-100819.CrossRefPubMedPubMedCentral

Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM: Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013, 369: 1502-1511. 10.1056/NEJMoa1306555.CrossRefPubMedPubMedCentral

Domanska K, Carlsson C, Bendahl PO, Nilbert M: Knowledge about hereditary nonpolyposis colorectal cancer; mutation carriers and physicians at equal levels. BMC Med Genet. 2009, 10: 30-10.1186/1471-2350-10-30.CrossRefPubMedPubMedCentral

Rinke ML, Mikat-Stevens N, Saul R, Driscoll A, Healy J, Tarini BA: Genetic services and attitudes in primary care pediatrics. Am J Med Genet A. 2014, 2: 449-455. 10.1002/ajmg.a.36339.CrossRef

Jbilou J, Halilem N, Blouin-Bougie J, Amara N, Landry R, Simard J: Medical genetic counseling for breast cancer in primary care: a synthesis of major determinants of physicians’ practices in primary care settings. Publ Health Genom. 2014, 4: 190-208. 10.1159/000362358.CrossRef

10.

Beery TA: Genetic and genomic testing in clinical practice: what you need to know. Rehabil Nurs. 2014, 2: 70-75. 10.1002/rnj.126.CrossRef

11.

Vassy JL, Lautenbach DM, McLaughlin HM, Kong SW, Christensen KD, Krier J, Kohane IS, Feuerman LZ, Blumenthal-Barby J, Roberts JS, Lehmann LS, Ho CY, Ubel PA, MacRae CA, Seidman CE, Murray MF, McGuire AL, Rehm HL, Green RC, MedSeq Project: The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine. Trials. 2014, 15: 85-10.1186/1745-6215-15-85.CrossRefPubMedPubMedCentral

12.

Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, Hall KP, Evers DJ, Barnes CL, Bignell HR, Boutell JM, Bryant J, Carter RJ, Keira Cheetham R, Cox AJ, Ellis DJ, Flatbush MR, Gormley NA, Humphray SJ, Irving LJ, Karbelashvili MS, Kirk SM, Li H, Liu X, Maisinger KS, Murray LJ, Obradovic B, Ost T, Parkinson ML, Pratt MR, et al: Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008, 456: 53-59. 10.1038/nature07517.CrossRefPubMedPubMedCentral

13.

Li H, Durbin R: Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010, 26: 589-595. 10.1093/bioinformatics/btp698.CrossRefPubMedPubMedCentral

14.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA: The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010, 20: 1297-1303. 10.1101/gr.107524.110.CrossRefPubMedPubMedCentral

15.

Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN: Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat. 2003, 21: 577-581. 10.1002/humu.10212.CrossRefPubMed

16.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS: A systematic approach to assessing the clinical significance of genetic variants. Clin Genet. 2013, 84: 453-463. 10.1111/cge.12257.CrossRefPubMedPubMedCentral

17.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE, Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med. 2008, 10: 294-300. 10.1097/GIM.0b013e31816b5cae.CrossRefPubMed

18.

Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE: Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012, 92: 414-417. 10.1038/clpt.2012.96.CrossRefPubMedPubMedCentral

19.

Lane WJ, Leshchiner I, Boehler S, Uy JM, Aguad M, Smeland-Wagman R, Green RC, Rehm HL, Kaufman RM, Silberstein LE, for The MedSeq Project: Comprehensive blood group prediction using whole genome sequencing data from the medSeq project [abstract]. In Proceedings of the 63 ^rd annual meeting of the American Society of Human Genetics. Boston, MA; 2013.,

20.

Aronson SJ, Clark EH, Babb LJ, Baxter S, Farwell LM, Funke BH, Hernandez AL, Joshi VA, Lyon E, Parthum AR, Russell FJ, Varugheese M, Venman TC, Rehm HL: The GeneInsight Suite: a platform to support laboratory and provider use of DNA-based genetic testing. Hum Mutat. 2011, 32: 532-536. 10.1002/humu.21470.CrossRefPubMedPubMedCentral

21.

Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR: ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014, 42: D980-D985. 10.1093/nar/gkt1113.CrossRefPubMed

22.

Aronson SJ, Clark EH, Varugheese M, Baxter S, Babb LJ, Rehm HL: Communicating new knowledge on previously reported genetic variants. Genet Med. 2012, 14: 713-719. 10.1038/gim.2012.19.CrossRefPubMedCentral

23.

Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O’Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG, American College of Medical Genetics and Genomics: ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013, 15: 565-574. 10.1038/gim.2013.73.CrossRefPubMedPubMedCentral

24.

Won HH, Kim HJ, Lee KA, Kim JW: Cataloging coding sequence variations in human genome databases. PLoS One. 2008, 3: e3575-10.1371/journal.pone.0003575.CrossRefPubMedPubMedCentral

25.

Cassa CA, Tong MY, Jordan DM: Large numbers of genetic variants considered to be pathogenic are common in asymptomatic individuals. Hum Mutat. 2013, 34: 1216-1220. 10.1002/humu.22375.CrossRefPubMedPubMedCentral

26.

Ohata T, Koizumi A, Kayo T, Shoji Y, Watanabe A, Monoh K, Higashi K, Ito S, Ogawa O, Wada Y, Takada G: Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family. Hum Genet. 1998, 103: 470-474. 10.1007/s004390050852.CrossRefPubMed

27.

Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A, Lango H, Frayling TM, Neumann RJ, Sherva R, Blech I, Pharoah PD, Palmer CN, Kimber C, Tavendale R, Morris AD, McCarthy MI, Walker M, Hitman G, Glaser B, Permutt MA, Hattersley AT, Wareham NJ, Barroso I: Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet. 2007, 39: 951-953. 10.1038/ng2067.CrossRefPubMedPubMedCentral

28.

Franks PW, Rolandsson O, Debenham SL, Fawcett KA, Payne F, Dina C, Froguel P, Mohlke KL, Willer C, Olsson T, Wareham NJ, Hallmans G, Barroso I, Sandhu MS: Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations. Diabetologia. 2008, 51: 458-463. 10.1007/s00125-007-0887-6.CrossRefPubMed

29.

Pagon RA, Adam MP, Bird TD: GeneReviews. http://www.ncbi.nlm.nih.gov/books/NBK1116/.,

30.

Orphanet: an online database of rare diseases and orphan drugs. http://www.orpha.net.,

31.

Tarczy-Hornoch P, Amendola L, Aronson SJ, Garraway L, Gray S, Grundmeier RW, Hindorff LA, Jarvik G, Karavite D, Lebo M, Plon SE, Van Allen E, Weck KE, White PS, Yang Y: A survey of informatics approaches to whole-exome and whole-genome clinical reporting in the electronic health record. Genet Med. 2013, 15: 824-832. 10.1038/gim.2013.120.CrossRefPubMedPubMedCentral

32.

Jamal SM, Yu JH, Chong JX, Dent KM, Conta JH, Tabor HK, Bamshad MJ: Practices and policies of clinical exome sequencing providers: Analysis and implications. Am J Med Genet A. 2013, 161A: 935-950. 10.1002/ajmg.a.35942.CrossRefPubMed

33.

Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, Stray-Pedersen A, Liu P, Wen S, Alcaraz W, Cui H, Walkiewicz M, Reid J, Bainbridge M: Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014, 18: 1870-1879. 10.1001/jama.2014.14601.CrossRef

34.

Dewey FE, Grove ME, Pan C, Goldstein BA, Bernstein JA, Chaib H, Merker JD, Goldfeder RL, Enns GM, David SP, Pakdaman N, Ormond KE, Caleshu C, Kingham K, Klein TE, Whirl-Carrillo M, Sakamoto K, Wheeler MT, Butte AJ, Ford JM, Boxer L, Ioannidis JP, Yeung AC, Altman RB, Assimes TL, Snyder M, Ashley EA, Quertermous T: Clinical interpretation and implications of whole-genome sequencing. JAMA. 2014, 10: 1035-1045. 10.1001/jama.2014.1717.CrossRef

35.

Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF: Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014, 18: 1880-1887.

36.

Vassy JL, Davis K, Robinson JO, Blumenthal-Barby J, Christensen KD, Green RC, McGuire AL, Ubel PA: Contextualization and Recommendation: How doctors and patients discuss whole-genome sequencing results [abstract]. In Proceedings of the 64 ^th annual meeting of the American Society of Human Genetics. San Diego, CA; 2014.,

Title: A systematic approach to the reporting of medically relevant findings from whole genome sequencing
Authors: Heather M McLaughlin
Ozge Ceyhan-Birsoy
Kurt D Christensen
Isaac S Kohane
Joel Krier
William J Lane
Denise Lautenbach
Matthew S Lebo
Kalotina Machini
Calum A MacRae
Danielle R Azzariti
Michael F Murray
Christine E Seidman
Jason L Vassy
Robert C Green
Heidi L Rehm
for The MedSeq Project
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2014
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-014-0134-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A systematic approach to the reporting of medically relevant findings from whole genome sequencing

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2014

A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency

Identification of transcription factors and single nucleotide polymorphisms of Lrh1 and its homologous genes in Lrh1-knockout pancreas of mice

Adult phenotype and further phenotypic variability in SRD5A3-CDG

A genomic copy number variant analysis implicates the MBD5 and HNRNPUgenes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion

A novel insertion mutation identified in exon 10 of the MEFV gene associated with Familial Mediterranean Fever

Paraganglioma and pheochromocytoma upon maternal transmission of SDHDmutations