New CNV Regions Identified in ITP Provide Evidence for Genetic Predisposition

Immune thrombocytopenia (ITP) is an autoimmune disease resulting from inhibition of megakaryopoiesis and destruction of platelets by platelet reactive autoantibodies. Adult-onset ITP usually exhibits a relapsing chronic course and is often associated with other disorders of autoimmune or infectious origin, including systemic lupus erythematosus (SLE), lymphoproliferative diseases, common variable immunodeficiency (CVID) disease, and human immunodeficiency virus (HIV) infection. The exact pathophysiology of ITP has not been fully elucidated. Heterogeneity in disease presentation and in response to immunosuppressive therapy suggests different underlying mechanisms; and thus justifies the investigation of relevant genetic associations. Here we tried to unravel the genetic background of the immune dysfunction in ITP by using SNP array technology.

We analyzed the blood samples of 12 adults (6 males and 6 females) with primary refractory ITP, by SNP array approach to identify candidate genomic regions. None of the patients showed clinical and laboratory findings of autoimmune diseases, malignancy or infections. All individuals were genotyped using Illumina Human HumanCytoSNP-12 BeadChip (300K). Whole genome SNP genotyping data were delineated using GenomeStudio software platform. The genotyping data was obtained by further analyzes in terms of copy number variation (CNV).

In total we observed 14 CNVs in 12 patients. All CNVs were on autosomal chromosomes; 8 duplications and 6 deletions (gain 2p, 9q, 13q, 14q, 17p, 17q, 20q; loss 5q, 7p, 7q, 15q, 17q, 19q). The rearrangements sizes were between 45.42 Mb and 1.08 Mb. Moreover in five patients the duplications were in the form of mosaic structural genomic rearrangements. These mosaic duplications were found at 17q21.31 (0.2 Mb), 2p23.2 (0.34 Mb), 9q21.2 (10.89 Mb), 9q31.2 (17.77 Mb), 14q13.2 (0.37 Mb), 17p12 (1.46 Mb), 20q11.21 (14.24 Mb). None of the detected CNV regions could be demonstrated in two independent cohorts of 30 individuals with non-hematological disorders and healthy controls.

Little is known on the genetic background of immune thrombocytopenia. Our aim was to investigate the impact of CNVs on the pathophysiology of ITP. We found several gains/losses in different chromosomal regions. However, the most striking result of our study was the detection of mosaic patterns that have been reported to most commonly associate with hematological cancers. These mosaic patterns may be associated with clonal expansion of T- or B-cells, leading to the immune dysfunction seen in ITP. Evaluation of the detected regions and their relation to B and T- cell clonality is ongoing. These preliminary results provide early evidence for the presence of predisposing CNVs in adult onset ITP.