Clinical Spectrum of LIG 4 Deficiency Is Broadened with Severe Dysmaturity, Primordial Dwarfism, and Neurological Abnormalities

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 LIG 4 . The p. S 205 L fs X 29 mutation results in lack of the nuclear localization signal and appears to be a null mutation. The second mutation p. K 635 R fs X 10 lacks the C ‐terminal region responsible for XRCC 4 binding and LIG 4 stability and activity, and therefore this mutant might be a null mutation as well or have very low residual activity. This is remarkable since L ig4 knockout mice are embryonic lethal and so far in humans no complete LIG 4 deficiencies have been described. This case broadens the clinical spectrum of LIG 4 deficiencies.