IP is mainly a sporadic condition, about 70% of affected individuals have IP as a result of a de novo pathogenic variant. Heterozygous, affected women have a 50% chance of transmitting the IKBKG/NEMO pathogenic variant at conception; however, male conceptuses with an IKBKG/NEMO loss-of-function variant miscarry.
Prenatal testing for pregnancies at increased risk is possible if the familial pathogenic variant has been identified. Analysis of IKBKG is complicated by the presence of a highly homologous pseudogene, IKBKGP1.
Molecular testing is performed in three steps:
- The search for the common 11.7 IKBKG/NEMO deletion that is present in around 65% of IP patients is performed using standardized PCR method avoiding the identification of non-pathogenic mutation in the pseudogene;
- The search for pathogenic variants including small intragenic deletions/insertions and missense, nonsense and splice site variants (8.6 % of IP patients) is performed using exon specific/gene specific PCR;
- Gene-targeted deletion/duplication analysis (4% of IP patients) is performed by QPCR analysis along the entire IKBKG/NEMO locus to evaluate partial copy number loss or copy number gain to reveal pathogenic variants due to aberrant recombination producing deletions involving IKBKG/NEMO, the IKBKG pseudogene and eventually the neighboring gene
Of note, the skewed X-chromosome inactivation often observed in the cells of IP patients prevent mRNA mutation analysis of IKBKG/NEMO gene.
A locus specific registry of IKBKG/NEMO mutations is available at https://databases.lovd.nl/shared/genes/IKBKG