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.

原发性免疫缺陷 (PI) 是免疫系统的遗传缺陷，如果不进行诊断和治疗，会导致慢性且通常危及生命的感染和/或危及生命的自身免疫。疑似 PI 但没有基因诊断的患者通常会经历昂贵、耗时且艰巨的诊断过程。这种延误诊断阻碍了适当的疾病管理和治疗，导致长期痛苦和生活质量下降。尽管下一代测序 (NGS) 可以让这些患者从这种诊断过程中解脱出来，但通常无法获得，主要是由于成本和交通不便。2019 年 1 月，Jeffrey Modell 基金会 (JMF) 为临床诊断为潜在 PI 的 Jeffrey Modell 中心网络 (JMCN) 患者启动了免费的基因测序试点计划。JMCN 内共有 21 个站点受邀参加。JMF 与 Invitae 合作，测试由 Invitae 的主要免疫缺陷小组组成，目前包括 207 个基因。向每位参与的医生分发了一份问卷，以评估获得基因测序的障碍以及测试后疾病管理和治疗的变化。在这项初步研究中测试了 158 名患者和 29 名家庭成员。21% 的疑似单基因疾病患者接受了分子诊断，其他人接受了可能有用的诊断线索。根据基因测序结果，45% 的患者临床诊断改变，40% 的疾病管理改变，36% 的治疗改变，62% 的遗传咨询改变。该试点项目的结果证明了 NGS 对 PI 的实用性、成本效益和至关重要的重要性，并在专家免疫学家的要求下为 PI 患者进行大规模基于序列的诊断提供了理由。