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.
Highlights
Primary immunodeficiencyPrimary immunodeficiencies (PI) [1, 2] are genetic disorders of the immune system that result in chronic, serious, and often life-threatening infections, and/or life-threatening autoimmunity if not diagnosed and treated [3, 4]
None of the patients referred for common variable immunodeficiency (CVID) received a molecular diagnosis from this panel, though one patient was found to be a heterozygous carrier of a TACI pathogenic mutation, which, while alone is not diagnostic, is considered a risk factor for CVID
By leveraging the vast Jeffrey Modell Centers Network (JMCN), which provides direct access to expert immunologists who harbor a backlog of clinically diagnosed patients in need of a genetic diagnosis, we demonstrated that their clinical expertise alone proves to be very effective in determining the need for next generation sequencing (NGS)
Summary
Primary immunodeficiencies (PI) [1, 2] are genetic disorders of the immune system that result in chronic, serious, and often life-threatening infections, and/or life-threatening autoimmunity if not diagnosed and treated [3, 4]. In addition to diseases as serious as severe combined immunodeficiency (SCID), manifestations of less severe PIs may include susceptibility to common infections, opportunistic infections, persistent or aberrant inflammation, and severe organ-specific autoimmune conditions. Recent studies have shown that PI may be more common than previously estimated [7] and that as much as 1% of the population may be affected with a PI when all types and varieties are considered [8]. Awareness of PI among physicians and the general public remains challenging, and there continues to be a need for improved and timely management of these conditions [14, 15]
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