Use of Whole Exome Sequencing to Diagnose Autosomal Recessive Immunodeficiency Disorder

Abstract

Immunodeficiency type 41 with lymphoproliferation and autoimmunity, also known as CD25 deficiency is a rare genetic disease of immune dysregulation showing autosomal recessive pattern of inheritance. The disease phenotype highly resembles Immune Dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) syndrome presenting with increased susceptibility to bacterial, fungal, viral infections, lymphoproliferation, eczema, enteropathy with villous atrophy and a variety of autoimmune manifestations. The disease is caused due to mutations in the IL2RA gene located on chromosome 1 Op 15.1 coding for the a-subunit (CD25) of the IL-2 receptor complex expressed on the surface of a variety ofT-cells, especially the FOXP3+ CD25+ regulatory T cells. The a- subunit along with the ~-subunit and y-subunit make the high efficiency receptor for IL-2. The IL-2 is an important cytokine affecting a variety of T-cell subsets. It is crucial for the development, proliferation and regulation of regulatory T -cells. Defects in the IL2RA gene cause an absence or deterioration of the IL-2 receptor leading to loss of T-cell regulation and immune tolerance resulting in the paradoxical combination of immunodeficiency and autoimmunity in those affected. This study was aimed at diagnosing an autosomal recessive disease showing symptoms of immunodeficiency. Whole exome sequencing (Illumina Hiseq 4000) was perfonned for screening of mutations in the genomic DNA of the patient. A novel splice donor site variant c.64+ 1 G> A was identified in the IL-2Ra gene in the proband. The in silico analysis ofthe variant predicted it to be pathogenic, however protein expression studies are recommended to understand the effect of variant on function and structure of the protein and its role in the disease.