| Summary: | The DNA ligase IV syndrome is a rare hereditary disorder associated with impaired DNA double-strand break repair mechanisms, associated with combined immunodeficiency. We investigated a 12-year old patient with obvious syndromic features, severe microcephaly, short stature, low body weight and bird-like facial features, resembling Seckel syndrome or Fanconi anemia with no signs of acute illness or malignancy.Diagnostic investigation included flow cytometry immunophenotyping and a custom HaloPlexHS (Agilent) NGS panel, to investigate mutations in genes involved in Bone Marrow Failure/Severe Combined Neutropenia, Anemias and Chromosome Breakage Syndrome. Sanger sequencing was performed to determine parental carrier status.Two variants in the LIG4 gene were identified, c.2440C > T (p.Arg814Ter) and c.1273_1278delAGAGAA (p.Arg425_Glu426del). LIG4 c.2440C > T is a nonsense heterozygous variant which prematurely terminates the protein, classified as pathogenic, and LIG4 c.1273_1278del is an in-frame deletion, classified as of uncertain significance according to ACMG recommendations. Compound heterozygous mutations in the LIG4 gene have been associated to DNA ligase IV syndrome, an autosomal recessive disorder caused by homozygous or compound heterozygous mutations. Parental testing revealed that LIG4 c.2440C > T variant was maternally inherited and the LIG4 c.1273_1278delAGAGAA variant was paternally inherited.Globally, approximately forty cases appear in literature, with patients portraying great phenotypic heterogeneity. With a prevalence of < 1/1000000 worldwide, DNA ligase IV syndrome is extremely rare and case reporting is crucial in disease understanding and monitoring.
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