Whole exome sequencing of adult Indians with apparently acquired Aplastic Anemia: initial experience at tertiary care hospital

Aplastic anaemia (AA) is a rare hypocellular bone marrow disease which can be acquired or constitutional. Nearly 10-30% patients with apparently acquired AA have mutations in telomerase reverse transcriptase gene (TERT) leading to bone marrow failure. The TERT plays a crucial role in regulating the telomerase ribonucleoprotein complex which otherwise causes short telomeres leading to AA. We used our benchmarked whole exome sequencing (WES) pipeline and systems bioinformatics approaches to identify sequence variants underlying AA in adult Indian subjects with apparently acquired AA. For 36 affected individuals, we sequenced coding regions to a mean coverage of 100× and a sufficient depth was achieved. The downstream validation and filtering was done to call the variants wherein we identified a host of candidate genes associated with AA who were treated with Cyclosporine A (CsA). Across all samples, six genes were shown to be associated with the AA phenotype with one non-coding SNP underlying intronic region as an exceptional case from interferon gamma ( IFNG ). While these variants (across the genes, viz. TERT (G/X), IFNG ( T/C), PIGA (T/X) or (T/A), NBS1/NBN (T/X), MPL (G/C) and CYP3A5) spanned across the subjects, a majority of control samples do not have these variants. We demonstrate the application of WES to discover the variants associated with CsA responders and non-responders in the Indian cohort.