Augmenting the Jeffrey Modell Criteria for Optimising Screening for Inborn Errors of Immunity

Area of Science:

• Immunology
• Genetics

Background:

• The Jeffrey Modell Foundation (JMF) warning signs are established for screening inborn errors of immunity (IEIs).
• However, JMF signs may lack sensitivity for non-infectious presentations of IEIs.

Purpose of the Study:

• To evaluate the effectiveness of JMF signs combined with additional clinical and laboratory parameters for guiding molecular screening of IEIs.
• To identify an optimal model for improving the diagnostic accuracy of IEI screening.

Main Methods:

• Retrospective analysis of 100 patients suspected of IEI undergoing whole-exome sequencing (WES).
• Evaluation of JMF signs alongside autoimmunity, autoinflammation, vaccine complications, fever with bi-cytopenia, consanguinity, absolute lymphocyte count, low naive T cell percentage, and hypogammaglobulinaemia.
• Development and validation of 32 models using combinations of signs and JMF scores, assessed via AIC score and WES results from 219 patients.

Main Results:

• JMF scores were significantly higher in patients with pathogenic variants compared to those without (3.54 ± 1.92 vs. 1.34 ± 1.28, p < 0.05).
• The best model, incorporating consanguinity, autoimmunity, vaccine complications, hypogammaglobulinaemia, and low naive T cell percentage with JMF, achieved 82% sensitivity and 67% specificity.
• This model showed improved specificity compared to JMF alone (61%).

Conclusions:

• The presence of any two from parental consanguinity, autoimmunity, vaccine complications, and low naive T cell percentage significantly enhances the specificity of JMF criteria.
• This combined approach improves the guidance for molecular screening in patients with suspected IEIs.