Hematopoietic stem cell transplantation in the era of next generation sequencing

Primary immune deficiency (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function leading to increased susceptibility to infections, disorders of immune regulation and malignancies. PID prevalence is estimated at 2-5:100.000. The incorporation of next generation sequencing (NGS) into routine immunological practice has enabled the identification of novel inborn errors of disease, helped define new categories of immune deficiency and extended the clinical spectrum associated with many long-recognised diseases. Indeed, sixteen years after the completion of the human genome project, the use of whole exome sequencing (WES) has turned into a primary diagnostic tool in cases of PIDs. Between 2012 and 2019, hundreds of WES were conducted at Hadassah Medical Center on pediatric patients with suspected PID. In about 60% of cases, a precise genetic diagnosis was found. A major strength of our translational work derives from the fact that our clinical practice comprises a large number of patients born to consanguineous families. Indeed, in collaboration with community physicians from Israel and the Palestinian Authority, we have identified new forms of inherited immune deficiency. The first disorders were identified by homozygocity mapping (ITK and the SP110 genes) and additional disorders were later discovered by whole exome sequencing (the CARD11, IKKβ, VPS45, EFL1, TPP2 and LAT deficiencies). The use of WES in suspected PID displays several advantages. First, WES enables the early diagnosis of affected, yet asymptomatic, family members, often before the onset of severe disease features, which significantly reduces the successful rate of hematopoietic stem cell transplantation (HSCT) if required. Characterization of disease-causing genes, together with a detailed immunological workup, both carried out in our institution, contribute to the understanding of novel mechanisms of immune disease and influence the clinical decision-making: the knowledge that these defects affect the hematopoietic system gave the confidence to proceed with HSCT and subsequently cure numerous patients of their disease. In the near future, the deep understanding of the biological basis of PIDs could lead to the development of novel therapeutic avenues.