Radiosensitive severe combined immunodeficiency (RS-SCID) is usually caused by defects in genes involved in DNA repair pathways such as DCLRE1C, PRKDC, and ligase IV. Additionally, because of the heightened sensitivity to ionizing radiation, haematopoetic stem cell transplantation (HSCT) conditioning regimes need careful consideration. Here we report the case of a male patient affected by LIGASE1 deficiency, a relatively rare and new type of autosomal recessive RS-SCID. The infant had absent T-cell receptor excision circles/κ-deleting recombination excision circles on newborn neonatal screening test (NNST). Second-tier testing confirmed severe T and B cell lymphopaenia with preserved natural killer (NK) numbers, suggesting a T-B-NK+ phenotype. Few naïve CD4 (117/uL), CD8 (30/uL), and B cells (10/uL) were identified in the peripheral blood. Recent thymic emigrants were 30%, suggesting reduced but not absent thymopoiesis. Accordingly, phytohaemagglutinin response was suboptimal but not absent. Additional investigations excluded fetomaternal engrafting (Y chromosome amplification in T cells) and Omenn’s syndrome (V-β T-cell receptor repertoire amplification was polyclonal). He was also noted to be persistently neutropenic and had transfusion-dependent anaemia, suggesting a complex phenotype. Extensive genetic testing identified a pathogenic maternally inherited LIG1 variant and a de novo deep intronic LIG1 variant in the paternal allele, which is undergoing further characterisation. Radiosensitivity assays confirmed DNA sensitivity to alkylating agents. On the basis of his RS-SCID diagnosis, at 4 months of age, the infant underwent HSCT from a 10/12 matched unrelated donor with reduced intensity conditioning using Flu/Cy/Campath. His HSCT was complicated by steroid refractory skin graft-versus-host-disease requiring transient ruxolitinib. Mixed donor–recipient chimerism was observed with 15% donor cells in the myeloid compartment. Lymphoid chimerism was 90%. He received a further CD34-selected boost at day +162, aiming to improve myeloid chimerism and minimise the need for transfusion. Thus far, the patient is transfusion independent but remains on intravenous immunoglobulin 6 months post HSCT. In the post-neonatal screening and rapid genetics era, the diagnosis of SCID has become more precise and efficient but challenges remain. Ligase 1 deficiency is an extremely rare form of RS-SCID, with only 6 cases in the literature. This case highlights the issues faced when diagnosing and transplanting rare conditions like RS-SCID due to a relatively newly described LIG1 deficiency.
