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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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Case Report: Profound newborn leukopenia related to a novel RAC2 variant
Geoffrey Hall1, Ágnes Donkó2, Cristina Pratt1
1Division of Allergy and Immunology, Department of Pediatrics, Duke University, Durham, NC, United States.
Frontiers in Pediatrics
|March 22, 2024
Summary
A novel RAC2 gene variant caused severe congenital neutropenia and immune deficiency in an infant. Functional testing confirmed the variant
Area of Science:
- Immunology
- Genetics
Background:
- Severe combined immunodeficiency (SCID) and congenital neutropenia are life-threatening conditions often diagnosed through newborn screening.
- Early diagnosis and genetic characterization are crucial for effective management of primary immunodeficiencies.
Observation:
- A 1-week-old infant presented with severe neutropenia, lymphopenia, and Escherichia coli bacteremia, initially suspected as SCID.
- Initial tests for SCID were inconclusive, and treatment with granulocyte colony-stimulating factor showed no improvement.
- Subsequent flow cytometry revealed increasing immune cell numbers, shifting the diagnosis towards congenital neutropenia and bone marrow failure syndromes.
Findings:
- Genetic testing identified a novel RAC2 variant (Q61K), a Ras-related GTPase crucial for immune cell function.
- Functional assays demonstrated that the Q61K variant led to elevated superoxide production and increased PAK1 binding, consistent with a constitutively active mutation.
- This RAC2 variant explains the observed neutropenia and immune dysfunction, highlighting phenotypic heterogeneity.
Implications:
- This case underscores the diagnostic challenges of novel genetic variants identified by next-generation sequencing panels.
- Functional assays are essential to confirm the pathogenicity of identified variants and understand their clinical impact.
- Accurate genetic diagnosis and functional characterization of RAC2 variants are vital for managing immune deficiencies and bone marrow failure syndromes.
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