MAP3K14

Inheritance Pattern: AR

Disease ID:MONDO:0018642

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0018642

Submitter: ClinGen

The relationship between MAP3K14 and NIK deficiency, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July, 2023. Note, at the time of curation, OMIM did not indicate an associated disease entity for this gene. MAP3K14 encodes mitogen-activated protein kinase kinase kinase 14, which is a serine/threonine protein-kinase. It is the central signaling component in the noncanonical nuclear factor-κB (NF-κB) pathway. NIK deficiency presents as a combined immunodeficiency characterized by recurrent infections, hypogammaglobulinemia, B lymphopenia, etc. (PMID: 25406581, 28580957). MAP3K14 was first reported in relation to autosomal recessive NIK deficiency in 2014 (Willmann et al, 2014; PMID: 25406581). This gene-disease relationship is supported by case-level and experimental data. Summary of Case Level Data (5 points): Three unrelated probands have been reported with three homozygous variants (2 missense and 1 frameshift) resulting in loss of function (PMIDs: 25406581, 29230214, 30445060). The mechanism of disease is biallelic loss of function. Only one frameshift variant is reported in ClinVar, and no coding variants in this gene are reported in gnomAD. Summary of experimental data (6 points): This gene-disease relationship is supported by several mouse models and in-vitro functional assays. NIK plays a central role in the noncanonical NFkB pathway and effects the downstream activation of NFkB2 (PMID: 28580957). It interacts with TRAF3, which is a negative regulator of NIK (PMID: 15084608). A mouse model that develops NIK deficiency spontaneously, identified as aly/aly (alymphoplasia), has been well characterized and studied by several groups. The causative variant is determined to be a missense variant, Gly855Arg, and the model recapitulates the human disease with features including hypogammagolbulinemia, B lymphopenia and absence of lymph nodes (PMID: 8299692, 10319865, 11069060, 11069060). Complete and conditional NIK knock-out mice have also been generated, which recapitulate NIK deficiency in humans (PMID: 11251123, 26116508, 26593098, 31481626, 36878304, 30070632). Introduction of wild-type NIK rescues the defective NFkB pathway in the knock-out mouse model and patient cells (PMID: 25406581, 10319865). In summary, the level of evidence to support the gene-disease relationship of MAP3K14 and autosomal recessive NIK deficiency is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Antibody Deficiencies GCEP on July 18, 2023 (SOP Version 9). This gene-disease pair was originally evaluated by the Antibody Deficiencies GCEP on July 18, 2023 (SOP Version 9). It was reevaluated on July 17, 2025 (SOP Version 11). Although a new animal model was published (PMID: 39519026), the classification did not change.

Inheritance Pattern: AR

Disease ID:MONDO:0018642

Submitter: Orphanet