DNA double-strand break repair via non-homologous end joining (NHEJ) is involved in recombination of immunoglobulin and T-cell receptor genes. Mutations in NHEJ components result in syndromes that are characterized by microcephaly and immunodeficiency. We present a patient with lymphopenia, extreme radiosensitivity, severe dysmaturity, corpus callosum agenesis, polysyndactily, dysmorphic appearance, and erythema, which are suggestive of a new type of NHEJ deficiency. We identified two heterozygous mutations in LIG4. The p.S205LfsX29 mutation results in lack of the nuclear localization signal and appears to be a null mutation. The second mutation p.K635RfsX10 lacks the C-terminal region responsible for XRCC4 binding and LIG4 stability and activity, and therefore this mutant might be a null mutation as well or have very low residual activity. This is remarkable since Lig4 knockout mice are embryonic lethal and so far in humans no complete LIG4 deficiencies have been described. This case broadens the clinical spectrum of LIG4 deficiencies.

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Keywords Immunodeficiency, LIG4, NHEJ, Non-homologous end joining, Primordial dwarfism
Persistent URL dx.doi.org/10.1002/humu.22436, hdl.handle.net/1765/62137
Journal Human Mutation
IJspeert, H, Warris, A, van der Flier, M, Reisli, I, Keles, S, Chishimba, S, … van der Burg, M. (2013). Clinical Spectrum of LIG4 Deficiency Is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities. Human Mutation, 34(12), 1611–1614. doi:10.1002/humu.22436