Global Expansion of Jeffrey's Insights: Jeffrey Modell Foundation's Genetic Sequencing Program for Primary Immunodeficiency

Abstract

Genetic disorders that impair the immune system, known as Primary Immunodeficiencies (PI), include over 450 single-gene inborn errors of immunity. Timely and appropriate diagnosis and treatment is vital to quality of life (QOL) and sometimes survival, as patients are susceptible to frequent, persistent, severe, and sometimes life-threatening infections or autoimmunity. Suspected PI patients that do not have a genetic diagnosis often endure a prolonged, onerous, inefficient, and expensive experience, known as a diagnostic odyssey. The resulting diagnostic delay prohibits proper disease management and treatment, causing unnecessary distress and diminished QOL. Next-generation sequencing (NGS) offers relief from the distress of the diagnostic odyssey, but because of cost and barriers to access, it is regularly unobtainable. The Jeffrey Modell Foundation (JMF) introduced "Jeffrey's Insights", a no-charge genetic sequencing pilot program, in January 2019 for patients within the Jeffrey Modell Centers Network (JMCN) with an underlying PI, but no genetic diagnosis. Building on the success of the pilot program, JMF expanded it globally to more than 400 Centers in the JMCN in early 2020. The most current version of Invitae's PI Panel available was used for this program. All participating clinicians were invited to complete a brief questionnaire assessing prior impediments to access and post-sequencing alterations in disease management and treatment. A total of 1,398 patients were tested, with 20.3% receiving a molecular diagnosis and many more receiving helpful diagnostic leads. Results obtained from genetic sequencing led to an alteration of clinical diagnosis, disease management, treatment, and genetic counseling in 39%, 38%, 35%, and 53% of patients, respectively. The global expansion of this program further underscores the crucial need for NGS for PI, along with its efficiency and potential cost savings. The results of this program to date further define rationale for the availability of comprehensive diagnostic NGS for patients with PI when requisitioned by an expert immunologist.

Keywords: Inborn Errors of Immunity (IEI); Jeffrey Modell Centers Network (JMCN); Jeffrey Modell Foundation (JMF); Next Generation Sequencing (NGS); Primary Immunodeficiency (PI); genetic sequencing; sequencing.

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Figure 1

Number of individuals tested in the Jeffrey’s Insights program based on geographic region. (A) Number of individuals tested globally by country in the program. The numbers indicate the number of individuals tested from each country. Countries are colored from light to dark to correspond to the relative number of individuals tested from low to high, respectively. (B) Number of individuals tested in the U.S. by state. The numbers indicate the number of individuals tested from each state. The color scale represents the relative number of individuals tested in each state with the light blue corresponding to a few individuals tested to dark blue indicating the states with the highest numbers of individuals tested.

Figure 2

The global diagnostic yield of the Jeffrey’s Insights Program. To determine the overall diagnostic yield, individuals that received a confirmed molecular diagnosis or likely molecular diagnosis were grouped together (labeled molecular diagnosis in the figure). Individuals with 1 P/LP and 1 VUS in an autosomal recessive gene were considered to have a likely diagnosis. Uncertain results were patients who only received variants of uncertain significance. Individuals who did not have any pathogenic, likely pathogenic, or variants of uncertain significance identified were grouped in the negative results. Individuals who were tested for an indication of common variable immunodeficiency (CVID) were excluded from this calculation due to the primarily multifactorial nature of this condition.

Figure 3

Diagnostic yield of the Jeffrey’s Insights program by geographic region. The diagnostic yield was calculated for patients from Asia, Europe, Latin America (LATAM), the Middle East (MidEast) plus Africa, and the United States (US) and Canada. Regional diagnostic yields were calculated the same way as the global diagnostic yield. Two out of 4 patients from Australia and New Zealand received a molecular diagnosis. However, these were excluded from the graph due to the low number of samples. n=number of samples.

Figure 4

Alteration rates of clinical diagnosis, disease management, treatment, and genetic counseling in patients after NGS testing. Through the questionnaire, participating clinicians reported that based on the results of NGS testing, clinical diagnosis was altered in 39% of patients, disease management was altered in 38% of patients, treatment was altered in 35% of patients, and genetic counseling was altered in 53% of patients.