Genetic basis of primary immunodeficiency diseases at PGIMER, Chandigarh-Medical conferences in karnataka 2017
Primary immunodeficiency disease (PID) are a heterogeneous group of genetic disorders characterized by defect in different components of the innate or adaptive immune system. More than 400 single gene defects that have been identified till date in various PIDs and the list expands each passing year.PIDs have been classified into 9 major groups as per the latest IUIS update in 2015. We performed a detailed analysis of the molecular diagnosis in patients with various immunodeficiency disorders diagnosed at PGIMER, Chandigarh over last 26 years (1991-2017).
Materials and methods- This was a retrospective review of the records of patients who were diagnosed to have a primary immunodeficiency disease and where a molecular defect was ascertained. Molecular diagnosis was performed using either conventional sanger sequencing of the putative gene or by next generation sequencing. Genetic sequencing was carried out at our centre and collaborating overseas centres.
Results- Molecular defects in various genes known to cause different PIDs were detected in 170 patients. X linked agammaglobulinemia with mutation in Bruton tyrosine kinase (BTK) gene was the most common disease group (48/170 patients, 28.2%). The second most common disease group was chronic granulomatous disease (CGD) and mutation in CYBB, NCF1 or NCF2 genes were seen in 29/164 patients (17%). Wiskott-Aldrich syndrome (WAS) constituted the 3rd most common group of PID (27/170 patients, 15.8%). Amongst patients with severe combined immunodeficiency, 27 patients were identified to have mutation in one of the several genes.IL2RG gene mutation was the most common (in 8 patients), followed by RAG1 (7 patients), RAG2 (5 patients), IL7RA (2 patients), ADA (2 patient), DCLRE1C (2 patients) and one PNP (1 patient). STAT3 gene mutation was seen in 5 patients while two patients each had gain of function mutation in STAT1 gene and one patient had a deletion in the DOCK-8 gene. Three patients with familial hemophagocytic lymphohistiocytosis (HLH) syndrome with mutations were identified. Mutation in PRF1 gene (2 patients) and STX11 gene (1 patient) were found. Four patients with Leucocyte adhesion defect (LAD) had mutation in ITGB2 gene. Seven patients with Hyper IgM syndrome were found to have mutation in CD40 ligand gene. Five patients with early onset systemic lupus erythematosus (SLE) were detected to have mutation in C1QA gene.
Conclusion - BTK gene mutation was the most common molecular defect amongst all PID patients at our centre followed by mutation in the WAS gene. Amongst patients with CGD, mutations in CYBB gene were similar number to mutations in NCF1 and NCF2 gene.