NUDCD3 was first reported in relation to autosomal recessive severe combined immunodeficiency and Omenn syndrome in 2024 (Chen, R. et al., PMID: 38787962). Severe combined immunodeficiency (SCID) occurs due to abnormal lymphocyte function, specifically T-cells and B-cells, thus resulting in increased susceptibility to infection. Omenn syndrome is a related disorder in which individuals typically have inflammation of the skin and viscera along with SCID-like lymphocyte abnormalities. A single homozygous hypomorphic missense variant, p.G52D, has been reported in 4 unrelated families of South Asian descent with a shared ancestral haplotype, suggesting it is likely a founder variant (PMID: 38787962). Two of the families were clinically described in previous publications (PMID: 15964782, 27577878). NUDCD3-related SCID and Omenn syndrome are characterized by erythroderma, alopecia, viral and bacterial infections, increased eosinophils, hyperIgE, hepatomegaly, abnormal leukocyte and lymphocyte counts, reduced or absent B cells, and T-cell abnormalities. There is inter- and intra-familial phenotypic variability. The mechanism of pathogenicity appears to be loss of function; however, more research is needed to establish the disease mechanism. This gene-disease relationship is also supported by experimental evidence, including in vitro functional assays, expression studies, and animal models (PMIDs: 38787962). NUDCD3 was shown to disrupt V(D)J recombination leading to abnormal T and B cell development in both in vitro and in vivo studies. Additionally, it was shown that NUDCD3 plays a key role in the redistribution of RAG1 from nucleoli, which is known to be necessary for RAG recombinase function.
In summary, there is limited evidence to support this gene-disease relationship. The experimental evidence was determined to be robust even with only a single variant being reporting in multiple consanguineous families from the same ethnic background; it has not been reported to occur in another population, and has not been replicated overtime. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen SCID-CID GCEP on 04/17/2025 as per SOP v11.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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