Primary immunodeficiency‐related genes in neonatal intensive care unit patients with various genetic immune abnormalities: a multicentre study in China

Abstract

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 nextgeneration sequencing (NGS)-based tests. We evaluated the PIDcausing 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.

Genetic diagnosis of inborn errors of immunity using clinical exome sequencing

“…Diagnostic yield varies among reports, which is due to the difference in the characteristics of study populations and the methods used ( Supplementary Table S3 ). Previous studies used targeted panel sequencing ( 20 , 21 ), CES ( 22 ), whole exome sequencing (WES) ( 23 , 24 ), or whole genome sequencing ( 25 ), and each method has its pros and cons. With targeted gene panel sequencing, in-depth sequencing of selected genes related to IEI is possible, which enables detection of low-level mosaic variants, whereas with methods that can test a large number of genes, diagnostic yield would be increased.…”

Genetic Diseases and Invasive Infections in Infants 100 Days or Younger

“…We found that 7 patients harbored mutations in 1 of the 4 genes (IL2RG, RAF1, IL10RA and HRAS), which could be mapped to the Janus kinase-signal transducer of activators of transcription pathway (hsa04630) and 5 of them was classified to PID (details in our previous study). 34 We observed that 5 genes (IL2RG, RAF1, IKBKG, FGFR2 and HRAS) were mapped to PI3K/Akt signaling pathway (hsa04151) and this pathway was shared by 3 PID patients and 4 non-PID ones. Recent studies [35][36][37] have begun to reveal a tightly-regulated system marked by extensive cross-talk among signaling pathways.…”

Genetic counselling considerations with genetic/genomic testing in Neonatal and Pediatric Intensive Care Units: A scoping review

“…A total of 170 articles were included in the final review (alphabetically ordered based on author in Supplementary Table 2). 1,2,7–50,55,56,68–189 A PRISMA flow diagram is presented to track the process and number of studies included and excluded (Figure 1).…”