Long-lasting, late-onset, and chronic idiopathic neutropenia project, February 2025 update
A project update from Dr Grigorios Tsaknakis.
The SWG-initiated research grant supported a study investigating the genetic underpinnings of chronic neutropenia in:
- Children (late-onset/long lasting neutropenia — LO/LL)
- Adults (chronic idiopathic neutropenia — CIN)
This was done through the application of whole exome sequencing (WES) in these patients.
The project aimed to analyze clinical and biological data from CIN adult patients and children with LO/LL neutropenia in order to identify whether:
- There is a potential constitutional/congenital background in some cases
- Neutropenia can be an epiphenomenon of immune dysregulation and associated underlying disorders
This analysis involved establishing correlations between neutropenia and immune-dysregulation genes.
Although analysis of WES data is still ongoing, initial analyses revealed that the classical genetic gene-disease model may not fully explain the etiology of neutropenia in all cases. While classical mutations in genes like SPINK5, MEFV, and BRCA1 were found in a small subset of patients (12%), suggesting a potential genetic cause, the majority of cases appear more complex.
Comparisons between patients and healthy controls for enrichment of rare deleterious variants in specific genes and their effect on disease manifestation have identified the RAD50 gene as significantly enriched in adult CIN patients. This gene is involved in double-stranded DNA break repair. SPINK5 also showed a trend towards increased frequency in both LO/LL children and CIN adults.
Further analyses using more sophisticated methods like SKAT and SKAT-O to assess gene-based burden scores are ongoing. However, preliminary data suggest an enrichment of variants in genes related to immune dysregulation pathways (PTPN22, LRBA, DOK2, DOK8, IL17RA, IFIH1, IL12RB2) in both LO/LL children and CIN adult patients compared to controls.
These findings suggest that a more complex interplay of genetic factors may contribute to the neutropenia phenotype in our cohorts. The observed enrichment of variants in immune-dysregulation pathways points towards potential underlying immune dysfunction as a contributing factor.
Future steps
Future steps involve analyzing a larger cohort of neutropenia patients to:
- Confirm these findings
- Further investigate the potential role of these genetic variants in the pathogenesis of chronic neutropenia through functional assays
This comprehensive analysis will provide valuable insights into the genetic landscape of these conditions and may inform future therapeutic approaches.
Through a future grant application, we will maintain the fruitful collaboration between the two research institutes towards tackling the complex pathophysiology of chronic idiopathic neutropenia.
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