Compound heterozygous NFKB1 missense variants in cis associated with immunodeficiency

Heterozygous pathogenic NFKB1 variants are one of the most frequent monogenic causes of disease in patients with inborn errors of immunity (IEI) and mainly compromise protein expression. NFKB1 encodes the precursor protein p105, which is processed into p50, the key transcription factor of canonical NF-κB1 signaling. Insufficiency of p105/p50 presents with immunodeficiency and autoinflammation. Here, we evaluated two NFKB1 missense variants, identified in compound heterozygosity in cis (c.[150A>C;156A>C]; p.[Gln50His;Lys52Asn]) in a patient with immunodeficiency. While the isomorphic Q50H variant enhanced the rather marginal defect of K52N, the combination of both caused a pathogenic protein damage in p50. Our findings highlight an inherent challenge when analyzing single variants 'isolated' from their genetic context. Particularly when filtering out additional variants, e.g. based on allele frequencies, pathogenic effects originating from compound heterozygosity may be overlooked.