LIG4 Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note):
Disease | LIG4 - DNA ligase IV deficiency |
|---|---|
Inheritance | Autosomal recessive |
Prevalence | <1 / 1 000 000 Source: Orphanet |
Rapid or full curation? | Rapid Full |
ClinGen SCID-CID expert panel, https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ec863c8-d668-4ebf-806e-e01f5a6407fe-2021-04-16T230148.883Z?page=1&size=25&search= | |
Clinical Validity Scoring Notes and points | LIG4 deficiency was first reported in a patient in 1990 (Plowman et al., PMID: 2400879). A fibroblast line from the patient was further investigated and identified mutated DNA LIG4 in relation to autosomal recessive SCID in 1999(Riballo et al., PMID 10395545). Since this first case was described, 27 further cases have been published with a broad spectrum of clinical features ranging from Microcephaly, developmental delay, lymphopenia, and other features. LIG4 is part of a end joining mechanism required in repairing DNA double stranded breaks. It is universally expressed and required to avert apoptosis and mutagenesis. DNA LIG4 also is involved in repairing programmed DNA double stranded breaks during lymphocyte receptor development.
Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants have been reported in 12 cases globally with combined immunodeficiency with T- and B- Lymphocytopenia, in at least 7 publications(PMID: 31604460, PMID 11779494, PMID 17224058, PMID 16088910, PMID 27063650, PMID 16358361, PMID 24123394). Probands described range in age of onset between 3 months to 48 years. The clinical manifestation of immunodeficiency may be due to a accumulation of DNA double-strand break which would lead to progressive apoptosis in lymphocyte progenitors of LIG4 patients based on the reduction of lymphocytes over time(PMID: 23722522). A family with three affected siblings showed varying cellular and molecular phenotypes with only one truly affected sibling suggesting the phenotype can dramatically vary(PMID: 27063650). This gene-disease association is supported by mouse models, functional alteration, and expression studies(PMID: 2013615, PMID:24889605, PMID: 109119933, PMID:11779494). Complete knockout of LIG4 in mice is embryological lethal and mutations described in humans are hypomorphic, leading to significantly impaired Non-homologous end joining but still maintaining some activity( PMID: 10911993).
In summary, LIG4 is definitively associated with autosomal recessive, severe combined immunodeficiency disease and combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time Source: SCID-CID expert panel, https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ec863c8-d668-4ebf-806e-e01f5a6407fe-2021-04-16T230148.883Z?page=1&size=25&search= |
Clinical Validity Points Total | 18 Source: SCID-CID expert panel, https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ec863c8-d668-4ebf-806e-e01f5a6407fe-2021-04-16T230148.883Z?page=1&size=25&search= |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: SCID-CID expert panel, https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ec863c8-d668-4ebf-806e-e01f5a6407fe-2021-04-16T230148.883Z?page=1&size=25&search= |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Unknown Several truncating variants reported, but gene is only comprised of two exons, and variants scored by SCID-CID expert panel are located in the last exon [(c.2440C>T (p.Arg814Ter), c.1271_1275del (p.Lys424fs), c.613del (p.Ser205fs)] , furthermore they note “Complete knockout of LIG4 in mice is embryological lethal and mutations described in humans are hypomorphic, leading to significantly impaired Non-homologous end joining but still maintaining some activity( PMID: 10911993).
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Penetrance Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID) | Reduced Source: PMID: 27063650 |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) |
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Severity |
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Clinical Features | Sources: |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary: | The LIG4 gene is associated with autosomal recessive DNA ligase IV deficiency, which is characterized by combined immunodeficiency with T- and B- lymphocytopenia, microcephaly, and developmental delay (PMID: 31604460, PMID 11779494, PMID 17224058, PMID 16088910, PMID 27063650, PMID 16358361, PMID 24123394). The severity and expressivity of the disorder is highly variable, even within families (PMID: ) |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, 06/14/2023 |