Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by 
mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory 
protein of nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, 
IP is due to recurrent or nonrecurrent deletions causing loss-of-function (LoF) 
of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus 
with segmental duplication and a high frequency of repetitive elements favor de 
novo aberrant recombination through different mechanisms producing genomic 
microdeletion. We report here a new microindel (c.436_471delinsT, p.Val146X) 
arising through a DNA-replication-repair fork-stalling-and-template-switching 
and microhomology-mediated-end-joining mechanism in a sporadic IP case. The LoF 
mutations of IKBKG/NEMO leading to IP include small insertions/deletions (indel) 
causing frameshift and premature stop codons, which account for 10% of cases. We 
here present 21 point mutations previously unreported, which further extend the 
spectrum of pathologic variants: 14/21 predict LoF because of premature stop 
codon (6/14) or frameshift (8/14), whereas 7/21 predict a partial loss of 
NEMO/IKKgamma activity (two splicing and five missense). We review how the 
analysis of IP-associated IKBKG/NEMO hypomorphic mutants has contributed to the 
understanding of the pathophysiological mechanism of IP disease and has provided 
important information on affected NF-kB signaling. We built a locus-specific 
database listing all IKBKG/NEMO variants, accessible at http://IKBKG.lovd.nl.