Submission Details

IKBKB was first reported in relation to an autosomal recessive IKBKB deficiency in 2013 (Pannicke U, et al., 2013, PMID:24369076). Symptoms usually appear in the first few months of life and patients present with a wide range of recurrent infections, failure to thrive and decreased antibody levels. Most patients have normal numbers of T and B cells but these are mostly naïve. All cases reported were homozygous for nonsense mutations. The curation of IKBKB relates to autosomal recessive severe combined immunodeficiency due to IKK2 deficiency with MONDO ID 0014267 includes both case-level and experimental evidence. The first publication described four cases from four families of Northern Cree ancestry in Canada. Sixteen other cases of Northern Cree ancestry were described by Cuvelier et al. (PMID: 30391351) and all cases with genetic data available confirmed the same nonsense mutation, which suggests a possible founder mutation. Several other cases were found in other populations with different nonsense mutations (PMIDs: 24679846, 32117824, 25216719, 25139357). There are no reports of symptomatic carriers and experimental data showed no effect on heterozygous siblings cells. A maximum score of 12 points for genetic evidence has been reached. This gene-disease association is also supported by expression, functional alteration and rescue models (PMIDs: 25139357 and 24369076). Absence of protein expression in PBMCs and EBV-transformed B cell lines from patients was found in immunoblot assays, despite mRNA levels remaining high. Also, patient cells transfected with wild-type protein or empty vector and subsequently stimulated showed that cells with WT protein express IKKB protein in the cytosol whereas the ones with empty vector do not. At the same time, Nf-κB expression in the nucleus increased with stimulation when WT gene is present. A different experiment showed normal levels of NF-κB activation by TNF-α were restored in cells from the patient that re-expressed IKKB, even when expression of IKKB was low. A score of 2.5 points for experimental evidence has been reached, increasing the total score to 14.5 points. In summary, IKBKB is definitively associated with autosomal recessive severe combined immunodeficiency due to IKK2 deficiency. In summary, this curation reached a level of "Definitive" as it has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date May 25, 2023 (SOP Version 9).