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Published on: March 30, 2018
Primary immunodeficiency-related genes in neonatal intensive care unit patients with various genetic immune
Tianwen Zhu1, Xiaohui Gong2, Fei Bei3
1Department of Neonatology Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai China.
Insights
Early diagnosis of primary immunodeficiency (PID) is crucial. Next-generation sequencing (NGS) aids in identifying PID subtypes, including JAK-STATopathies, enabling targeted treatments for better outcomes.
Area of Science:
- Immunology
- Genetics
Background:
- Phenotype-based classification of primary immunodeficiency (PID) presents diagnostic challenges.
- Timely and effective treatment for PID is often hindered by diagnostic ambiguity.
Purpose of the Study:
- To investigate the characteristics of early-onset PID.
- To propose a JAK-STATopathy subgroup based on molecular defects.
Main Methods:
- Retrospective review of 72 patients under 100 days old with immune-related phenotypes.
- Definitive molecular diagnosis using next-generation sequencing (NGS).
- Evaluation of PID-causing genes, clinical parameters, and JAK-STAT signaling pathway genes.
Main Results:
- PID identified in 34.72% of patients; 180-day mortality was 26.39%.
- Early onset (≤3.5 days) significantly correlated with higher 180-day mortality (P=0.009).
- Combined immunodeficiency with syndromic features was the most common PID class (60%). Life-threatening infections increased PID likelihood (OR=2.864).
- Twelve patients had JAK-STAT pathway defects; seven were classified as PID, presenting as immunological emergencies with severe infections and thrombocytopenia, leading to four early deaths.
Conclusions:
- NGS is effective for etiological diagnosis of complex early-life immune disorders.
- Pathway-based classification of PID can address heterogeneity and guide targeted therapies.
Objectives:
The present phenotype-based disease classification causes ambiguity in diagnosing and determining timely, effective treatment options for primary immunodeficiency (PID). In this study, we aimed to examine the characteristics of early-onset PID and proposed a JAK-STATopathy subgroup based on their molecular defects.
Methods:
We reviewed 72 patients (< 100 days) retrospectively. These patients exhibited various immune-related phenotypes and received a definitive molecular diagnosis by next-generation sequencing (NGS)-based tests. We evaluated the PID-causing genes and clinical parameters. We assessed the genes that shared the JAK-STAT signalling pathway. We also examined the potential high risks related to the 180-day death rate.
Results:
We identified PID disorders in 25 patients (34.72%, 25/72). The 180-day mortality was 26.39% (19/72). Early onset of disease (cut-off value of 3.5 days of age) was associated with a high 180-day death rate (P = 0.009). Combined immunodeficiency with associated or syndromic features comprised the most common PID class (60.00%, 15/25). Patients who presented life-threatening infections were most likely to exhibit PID (odds ratio [OR] = 2.864; 95% confidence interval [CI]: 1.047-7.836). Twelve out of 72 patients shared JAK-STAT pathway defects. Seven JAK-STATopathy patients were categorised as PID. They were admitted to NICUs as immunological emergencies. Most of them experienced severe infections and thrombocytopenia, with 4 succumbing to an early death.
Conclusions:
This study confirmed that NGS can be utilised as an aetiological diagnostic method of complex immune-related conditions in early life. Through the classification of PID as pathway-based subtypes, we see an opportunity to dissect the heterogeneity and to direct targeted therapies.
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