DNA Ligase IV – Dubowitz syndrome

Dubowitz syndrome is an autosomal recessive disorder characterized by microcephaly, growth failure, and cancer predisposition. Although over 200 clinical cases have been described, the genetic basis remained undefined until recent studies linked DNA non-homologous end-joining (NHEJ) defects to this phenotype. LIG4 (HGNC:6601), encoding DNA ligase IV, has emerged as a candidate gene in a subset of patients with this syndrome and overlapping immunodeficiency.

To date, four unrelated probands have been reported ([PMID:23372718]; [PMID:24892279]). In the initial report, fibroblasts from a single Dubowitz syndrome patient exhibited hypersensitivity to ionizing radiation, bleomycin, and doxorubicin, with intact checkpoint signaling. Sequencing identified compound heterozygous LIG4 c.613del (p.Ser205LeufsTer?) variants, implicating LIG4 deficiency in the clinical presentation ([PMID:23372718]).

A subsequent exome sequencing study of three individuals, including a brother–sister pair, revealed compound heterozygous LIG4 variants c.2440C>T (p.Arg814Ter) and c.613del in the siblings, with confirmed segregation of both alleles in two affected relatives ([PMID:24892279]). The third patient harbored a large 17q24.2 deletion spanning PRKAR1A, suggesting genetic heterogeneity but reinforcing LIG4’s role in a subset of cases.

Patient-derived fibroblasts consistently displayed defective repair of DNA double-strand breaks by NHEJ while maintaining normal responses to cross-linking agents, indicating a specific end-joining defect. Complementation with wild-type LIG4 fully rescued the DNA repair phenotype, demonstrating a direct loss-of-function mechanism ([PMID:23372718]).

Mechanistically, LIG4 deficiency compromises DNA end ligation, leading to genomic instability and the clinical features of microcephaly and growth delay. The concordance between cellular hypersensitivity assays and genetic findings confirms haploinsufficiency of DNA ligase IV as the pathogenic mechanism.

Together, these data meet moderate ClinGen clinical validity criteria: four probands, segregation in two siblings, and concordant functional rescue experiments. Genetic testing for LIG4 variants is recommended in patients with Dubowitz-like features to inform diagnostic, management, and counseling strategies. Key take-home: DNA ligase IV mutation screening refines diagnosis and guides care in a subset of Dubowitz syndrome cases.

References

• PLoS One • 2013 • Identification of the DNA repair defects in a case of Dubowitz syndrome. PMID:23372718
• PLoS One • 2014 • Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders. PMID:24892279

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