Mutations disrupting the kinase domain of IKKa lead to immunodeficiency and immune dysregulation in humans

IKKa, encoded by CHUK, is crucial in the non-canonical NF-?B pathway and part of the IKK complex activating the canonical pathway alongside IKKß. The absence of IKKa causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKa-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKa in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-?B activation was profoundly diminished in stromal and immune cells while the canonical pathway was unexpectedly partially impaired. Reintroducing wt CHUK restored non-canonical NF-?B activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-?B pathway deficiencies. Thus, this is the first case of biallelic CHUK mutations disrupting IKKa kinase function, broadening non-canonical NF-?B defect understanding, and suggesting IKKa's role in canonical NF-?B target gene expression in humans. Overall design: SV40-fibroblasts were stimulated with human TNFalpha 10 ng/mL or Poly I:C 10 ug/mL for 6h or left unstimulated and RNA were harvested with a DNAse digestion step. RNA sequencing was performed on total RNA extracts.