Biallelic germline variants in NSMCE3 were first reported in relationship to Lung disease, immunodeficiency and chromosome breakage syndrome in 2016 (PMID: 27427983). NSMCE3 is a component of the SMC5/6 complex, which has roles in maintenance of chromosome integrity and genomic stability. In the initial report, four patients from two families were identified due to severe lung disease following multiple virus-induced pneumonias. Heterozygous carriers have not been shown to have a clinical phenotype. Further testing identified chromosomal breakage in cultured lymphocytes, as well as a combined T and B cell dysfunction with recurrent infections. Subsequent studies involving five patients with biallelic NSMCE3 missense variants did not reveal immunodeficiency; though all presented with severe lung disease (PMID: 33741030). All five patients were homozygous for a single missense variant in NSMCE3 that was previously identified in the initial report (PMID: 27427983). Based on this information, it is hypothesized patients with biallelic variants in NSMCE3 display variable expressivity of immune defects. Finally, there is limited research investigating the relationship between NSMCE3 and the immune system, therefore no experimental evidence was included in this curation.
In summary, there is limited evidence to support the immunodeficiency component of this gene-disease relationship.
This classification was approved by the ClinGen SCID-CID Working Group on 6/20/2024 (SOP Version 9).
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