Hypomorphic SCID Due to LIG4 Deficiency Not Detected on Newborn Screening

DNA ligase IV (LIG4) is essential for repairing breaks in double-stranded DNA via nonhomologous end-joining in developing lymphocytes and is particularly important for V(D)J recombination. First described in the early 2000s, LIG4 deficiency is an autosomal recessive disorder characterized by hypomorphic T-B-NK+ severe combined immunodeficiency (SCID), as well as growth restriction with marked microcephaly, radiosensitivity, developmental delay, bone and skin abnormalities, and increased risk of hematologic malignancy. We describe a case of hypomorphic SCID due to LIG4 deficiency missed on newborn screening. A 6-month-old male was referred to genetics given severe growth restriction, with microcephaly out of proportion to weight (weight Z-score −3.5, head circumference Z-score −7). He was born at 37 weeks’ gestation after induction of labor for growth restriction, with a birth weight of 3 lb 14 oz. Pregnancy was otherwise uncomplicated. He had 2 normal Pennsylvania newborn screens for SCID. He had no infectious history and was meeting milestones. There was no family history of immunodeficiency or growth failure. Trio exome sequencing identified compound heterozygous likely pathogenic variants in LIG4: a maternally inherited missense variant (c.743C>T, p.(Pro248Leu) and a paternally inherited frameshift variant (c.1512_1513dup, p.(Arg505Leufs*9)). He was then referred to immunology. Lymphocyte subsets revealed T and B cell lymphopenia: CD3 451 cells/µL, CD4 158 cells/µL (40% naive), CD8 222 cells/µL, and CD19 345 cells/µL, with normal natural killer (NK) cells. T cell proliferation to PHA mitogen stimulation and TCR V-beta spectratyping were normal. T cell receptor excision circles (TRECs) were low at 1,059 copies/µL, meeting criteria for hypomorphic SCID. DNA repair assessment in lymphocytes testing demonstrated defective repair in double-stranded DNA breaks at 24 hours post-irradiation, confirming radiosensitivity. He had no evidence of Omenn syndrome or maternal engraftment. He began immunoglobulin replacement therapy and fluconazole and trimethoprim-sulfamethoxazole prophylaxis. He subsequently underwent maternal haploidentical TCRab/CD19-depleted peripheral stem cell transplant, conditioned with thymoglobulin, low-dose treosulfan, low-dose cyclophosphamide, and fludarabine, a modified regimen considering his DNA repair defect. He is approximately D+50 and recovering from a transplant outpatient. This case highlights a case of SCID missed on newborn screening, despite low TRECs at diagnosis. We also report two previously unpublished variants leading to LIG4 deficiency.