Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
LIG4–DNA ligase IV deficiency is a rare autosomal recessive disorder marked by microcephaly, primordial growth failure, pancytopenia, combined immunodeficiency, cellular radiosensitivity, and a predisposition to lymphoid malignancies (PMID:27717373). Initial reports described adolescent and pediatric probands with slowly progressing immunodeficiency masked by warts, short stature, and microcephaly, leading to a diagnosis confirmed by delayed DNA double‐strand break repair kinetics and rescue by wild-type LIG4 in patient fibroblasts (PMID:26172957).
Genetic evidence includes novel compound heterozygous and homozygous frameshift and nonsense variants identified through whole‐exome sequencing in multiple unrelated probands. To date, over 30 patients from at least 10 families have been reported with biallelic truncating (e.g., c.1738C>T (p.Arg580Ter)) and hypomorphic missense variants (PMID:26762768; PMID:15333585). All cases follow an autosomal recessive inheritance consistent with loss-of-function.
Segregation analysis demonstrates co-segregation of LIG4 variants with disease in multiple pedigrees, including two affected siblings in an asymptomatic carrier study (PMID:27063650) and concordant disease in brothers undergoing hematopoietic stem cell transplantation (PMID:31604460), supporting the genotype–phenotype relationship (segregation in at least 3 affected relatives).
Functional studies underscore the mechanistic basis of LIG4 deficiency. Patient-derived fibroblasts exhibit delayed repair of γ-irradiation–induced double‐strand breaks, which is rescued by complementation with wild-type LIG4 (PMID:26172957). A knock-in mouse model homozygous for the R278H mutation recapitulates growth retardation, radiosensitivity, and leaky SCID, illustrating that hypomorphic LIG4 variants impair non-homologous end-joining in vivo (PMID:20133615).
The phenotypic spectrum ranges from classical SCID with early-onset infections to presentations dominated by microcephaly and developmental delay without overt immunodeficiency, as reported in adolescent and adult patients (PMID:39953892). A founder effect for the p.Arg278Leu variant in Chinese cohorts highlights population-specific alleles and underscores the need for targeted genetic screening (PMID:34630384).
Clinical management relies on immunophenotyping, radiosensitivity assays, and molecular diagnostics. Hematopoietic stem cell transplantation offers a curative option; variable conditioning regimens have yielded divergent outcomes, emphasizing the importance of early genetic diagnosis to optimize transplantation timing and regimens (PMID:31604460).
In summary, autosomal recessive pathogenic variants in LIG4 cause DNA ligase IV deficiency, characterized by impaired DNA repair, immunodeficiency, and developmental anomalies. Integration of next-generation sequencing, functional assays, and family studies is critical for accurate diagnosis, guiding timely interventions and genetic counseling.
Gene–Disease AssociationStrongOver 30 affected individuals from >10 families, multi-family segregation (3 affected relatives) and functional complementation in patient fibroblasts ([PMID:26172957]). Genetic EvidenceStrongBiallelic truncating and hypomorphic variants in >30 probands across autosomal recessive families; segregation in 3 relatives. Functional EvidenceStrongPatient fibroblast rescue of DNA repair defect ([PMID:26172957]) and knock-in R278H mouse model recapitulating phenotype ([PMID:20133615]). |