NUDCD3

Inheritance Pattern: AR

Disease ID:MONDO:0015974

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0015974

Submitter: ClinGen

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.