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01-06-2020 | Primary Immunodeficiency | Original Article

Jeffrey’s insights: Jeffrey Modell Foundation’s global genetic sequencing pilot program to identify specific primary immunodeficiency defects to optimize disease management and treatment

Authors: Jessica Quinn, Vicki Modell, Jennifer Holle, Rebecca Truty, Swaroop Aradhya, Britt Johnson, Jordan Orange, Fred Modell

Published in: Immunologic Research | Issue 3/2020

Abstract

Primary immunodeficiencies (PI) are genetic defects of the immune system that result in chronic and often life-threatening infections and/or life-threatening autoimmunity if not diagnosed and treated. Patients with a suspected PI, but without a genetic diagnosis, commonly undergo a diagnostic odyssey that is costly, time-consuming, and arduous. This delay in diagnosis prevents appropriate disease management and treatment, contributing to prolonged suffering and decreased quality of life. Although next generation sequencing (NGS) can provide these patients with relief from such a diagnostic odyssey, it is often unavailable, mainly due to cost and inaccessibility. In January 2019, the Jeffrey Modell Foundation (JMF) launched a free genetic sequencing pilot program for Jeffrey Modell Centers Network (JMCN) patients clinically diagnosed with an underlying PI. A total of 21 sites within the JMCN were invited to participate. JMF collaborated with Invitae, and testing was comprised of Invitae’s Primary Immunodeficiency Panel, which currently includes 207 genes. A questionnaire was disseminated to each participating physician to evaluate barriers to access to genetic sequencing and changes in disease management and treatment after testing. One hundred fifty-eight patients and 29 family members were tested in this pilot study. Twenty-one percent of patients with a suspected monogenic disorder received a molecular diagnosis, and others received potentially useful diagnostic leads. Based on the results of genetic sequencing, clinical diagnosis was altered in 45% of patients, disease management was altered in 40%, treatment was altered in 36%, and genetic counseling was altered in 62%. The results of this pilot program demonstrate the utility, cost-efficiency, and critical importance of NGS for PI and make the case for broad scale sequence–based diagnostics for PI patients when requested by expert immunologists.

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Modell V. The impact of physician education and public awareness on early diagnosis of primary immunodeficiencies. Immunol Res. 2007;38:43–7.CrossRef

Modell F. Immunology today and new discoveries: building upon legacies of Dr. Robert A. Good. Immunol Res. 2007;38:48–50.CrossRef

Cunningham-Rundles C, Ponda PP. Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat Rev Immunol. 2005;5:880–92.CrossRef

Cooper MA, Pommering TL, Koranyi K. Primary immunodeficiencies. Am Fam Physician. 2003;68:2001–8.PubMed

BousfihaA JL, Al-HerzW AF, Casanova JL, Chatila T, et al. The 2015 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2015;35:727–38. https://doi.org/10.1007/s10875-015-0198-5.CrossRef

Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40:24–64. https://doi.org/10.1007/s10875-019-00737-x.CrossRefPubMedPubMedCentral

Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, et al. Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol. 2013;33(1):1–7.CrossRef

Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007;27(5):497–502.CrossRef

Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 2017;139(1):232–45. https://doi.org/10.1016/j.jaci.2016.05.042.CrossRefPubMed

10.

Rider NL, Kutac C, Hajjar J, Scalchunes C, Seeborg FO, Boyle M, et al. Health-related quality of life in adult patients with common variable immunodeficiency disorders and impact of treatment. J Clin Immunol. 2017;37(5):461–75. https://doi.org/10.1007/s10875-017-0404-8.CrossRefPubMedPubMedCentral

11.

Quinti I, Di Pietro C, Martini H, Pesce AM, Lombardi F, Baumghartner M, et al. Health related quality of life in common variable immunodeficiency. Yonsei Med J. 2012;53(3):603–10. https://doi.org/10.3349/ymj.2012.53.3.603.CrossRefPubMedPubMedCentral

12.

Casanova JL, Abel L, Quintana-Murci L. Immunology taught by human genetics. Cold Spring Harb Symp Quant Biol. 2013;78:157–72. https://doi.org/10.1101/sqb.2013.78.019968.CrossRefPubMed

13.

Meyts I, Bosch B, Bolze A, Boisson B, Itan Y, Belkadi A, et al. Exome and genome sequencing for inborn errors of immunity. J Allergy Clin Immunol. 2016;138(4):957–69. https://doi.org/10.1016/j.jaci.2016.08.003.CrossRefPubMedPubMedCentral

14.

Modell V, Gee B, Lewis DB, Orange JS, Roifman CM, Routes JM, et al. Global study of primary immunodeficiency diseases (PI)—diagnosis, treatment, and economic impact: an updated report from the Jeffrey Modell Foundation. Immunol Res. 2011;51:61–70.CrossRef

15.

Modell F, Puente D, Modell V. From genotype to phenotype. Further studies measuring the impact of a physician education and public awareness campaign on early diagnosis and management of primary immunodeficiencies. Immunol Res. 2009;44(1–3):132–49.CrossRef

16.

Sawyer SL, Hartley T, Dyment DA, Beaulieu CL, Schwartzentruber J, Smith A, et al. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet. 2016;89(3):275–84. https://doi.org/10.1111/cge.12654.CrossRefPubMed

17.

Yska HAF, Elsink K, Kuijpers TW, Frederix GWJ, van Gijn ME, van Montfrans JM. Diagnostic yield of next generation sequencing in genetically undiagnosed patients with primary immunodeficiencies: a systematic review. J Clin Immunol. 2019;39:577–91. https://doi.org/10.1007/s10875-019-00656-x.CrossRefPubMedPubMedCentral

18.

Heimall JR, Hagin D, Hajjar J, Henrickson SE, Hernandez-Trujillo HS, Tan Y, et al. Use of genetic testing for primary immunodeficiency patients. J Clin Immunol. 2018;38:320–9. https://doi.org/10.1007/s10875-018-0489-8.CrossRefPubMed

19.

Modell V, Orange JS, Quinn J, Modell F. Global report on primary immunodeficiencies: 2018 update from the Jeffrey Modell Centers Network on disease classification, regional trends, treatment modalities, and physician reported outcomes. Immunol Res. 2018;66:367–80. https://doi.org/10.1007/s12026-018-8996-5.CrossRefPubMed

20.

Lincoln SE, Kobayashi Y, Anderson MJ, et al. A systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian cancer genes in more than 1000 patients. J Mol Diagn. 2015;17(5):533–44. https://doi.org/10.1016/j.jmoldx.2015.04.009.

21.

Nykamp K, Anderson M, Powers M, et al. Correction: Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med. 2020;22(1):240. https://doi.org/10.1038/s41436-019-0624-9.CrossRefPubMed

22.

Bogaert DJA, Dullaers M, Lambrecht BN, Vermaelen KY, de Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53:575–90.CrossRef

23.

Modell V, Quinn J, Ginsberg G, Gladue R, Orange J, Modell F. Modeling strategy to identify patients with primary immunodeficiency utilizing risk management and outcome measurement. Immunol Res. 2017;65:713–20. https://doi.org/10.1007/s12026-017-8907-1.CrossRefPubMed

24.

Agency for Healthcare Research and Quality. http://www.hcup.ahrq.gov 2015.

25.

Aetna Member Navigator. http://www.aetna.com 2015.

26.

Centers for Medicare and Medicaid Services. Berenson-eggers type of service (BETOS). 2015. https://www.cms.gov/Medicare/Coding/HCPCSReleaseCodeSets/BETOS.html.

27.

Centers for Medicare and Medicaid Services. Medicare current beneficiary survey (MCBS). 2015. https://www.cms.gov/Research-Statistics-Data-and-Systems/Research/MCBS/index.html?redirect=/mcbs.

28.

Congressional Budget Office. Factors underlying the growth in Medicare’s spending for physicians’ services. 2007. Retrieved 28 Apr 2010, from http://www.cbo.gov/ftpdocs/81xx/doc8193/06-06-MedicareSpending.pdf.

29.

Bundorf KM, Royalty A, Baker LC. Health care cost growth among the privately insured. Health Aff. 2009;28(5):1294–304.CrossRef

30.

TruvenHealth Analytics Healthcare spending index for employer-sponsored insurance. 2014.

31.

Fronstin P. Sources of health insurance and characteristics of the uninsured: analysis of the March 2013 current population survey, vol 390. EBRI (Employee Benefit Research Institute) Issue Brief No. 390, 2013, Washington, DC; 2013. p. 1–36.

32.

Health Care Cost Institute (HCCI) 2014 Health Care Cost and Utilization Report 2015. http://www.healthcostinstitute.org/files/2014%20HCCUR%2010.29.15.pdf.

33.

Rae W, Ward D, Mattocks C, Pengelly RJ, Eren E, Patel SV, et al. Clinical efficacy of a next-generation sequencing gene panelfor primary immunodeficiency diagnostics. Clin Genet. 2018;93:647–55. https://doi.org/10.1111/cge.13163.CrossRefPubMed

34.

Bisgin A, Boga I, Yilmaz M, Bingol G, Altintas D. The utility of next-generation sequencing for primary immunodeficiency disorders: experience from a clinical diagnostic laboratory. Biomed Res Int. 2018;2018:9647253. Published 2018 May 16. https://doi.org/10.1155/2018/9647253.CrossRefPubMedPubMedCentral

35.

Moens LN, Falk-Sorqvist E, Asplund AC, Bernatowska E, Smith CIE, et al. Diagnostics of primary immunodeficiency diseases: a sequencing capture approach. PLoS One. 2014;9(12):e114901. https://doi.org/10.1371/journal.pone.0114901.CrossRefPubMedPubMedCentral

36.

Nicolosi P, Holle J, Truty R, Yu H, Hartshorne C, Martin S, et al. Expanded genetic testing for primary immunodeficiencies: findings from a 207-gene next-generation sequencing panel. San Diego: Poster presented at American Society of Human Genetics meeting; 2018.

Title: Jeffrey’s insights: Jeffrey Modell Foundation’s global genetic sequencing pilot program to identify specific primary immunodeficiency defects to optimize disease management and treatment
Authors: Jessica Quinn
Vicki Modell
Jennifer Holle
Rebecca Truty
Swaroop Aradhya
Britt Johnson
Jordan Orange
Fred Modell
Publication date: 01-06-2020
Publisher: Springer US
Keyword: Primary Immunodeficiency
Published in: Immunologic Research / Issue 3/2020
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI: https://doi.org/10.1007/s12026-020-09131-x

At a glance: The STEP trials

Springer Medicine

Jeffrey’s insights: Jeffrey Modell Foundation’s global genetic sequencing pilot program to identify specific primary immunodeficiency defects to optimize disease management and treatment

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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