Ligase IV syndrome can present with microcephaly and radial ray anomalies similar to Fanconi anaemia plus fatal kidney malformations

Eur J Med Genet. 2020 Sep;63(9):103974. doi: 10.1016/j.ejmg.2020.103974. Epub 2020 Jun 12.


Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum. We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, severe renal anomalies and skeletal abnormalities, including radial ray defects. Autozygosity mapping and exome sequencing identified a novel homozygous frameshift variant in LIG4, c.597_600delTCAG, p.(Gln200LysfsTer33), which segregated in the family. LIG4 is encoded by a single exon and so this frameshift variant is predicted to result in a protein truncated by 678 amino acids. This is the shortest predicted LIG4 protein product reported and correlates with the most severe clinical phenotype described to date. We note the clinical overlap with Fanconi anemia and suggest that LIG4 syndrome is considered in the differential diagnosis of this severe developmental disorder.

Keywords: Acrorenal syndrome; Cystic dysplastic kidneys; Fanconi anaemia; LIG4; Microcephaly; Radial ray defects.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Consanguinity
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / pathology
  • DNA Ligase ATP / genetics*
  • Fanconi Anemia / genetics*
  • Fanconi Anemia / pathology
  • Female
  • Fetus / abnormalities
  • Frameshift Mutation
  • Growth Disorders / genetics*
  • Growth Disorders / pathology
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / pathology
  • Infant, Newborn
  • Male
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Multicystic Dysplastic Kidney / genetics*
  • Multicystic Dysplastic Kidney / pathology
  • Phenotype*
  • Pregnancy
  • Radius / abnormalities*
  • Radius / embryology


  • LIG4 protein, human
  • DNA Ligase ATP

Supplementary concepts

  • LIG4 Syndrome