Microdeletion/duplication at the Xq28 IPlocuscauses a de novoIKBKG/NEMO/IKKgammaexon4_10 deletion in families with incontinentia pigmenti

Abstract

The Incontinentia Pigmenti (IP) locus contains the IKBKG/NEMO/IKKgamma gene and its truncated pseudogene copy, IKBKGP/deltaNEMO. The major genetic defect in IP is a heterozygous exon4_10 IKBKG deletion (IKBKGdel) caused by a recombination between two consecutive MER67B repeats. We analyzed 91 IP females carrying the IKBKGdel, 59 of whom carrying de novo mutations (65%). In eight parents, we found two recurrent nonpathological variants of IP locus, which were also present as rare polymorphism in control population: the IKBKGPdel, corresponding to the exon4_10 deletion in the pseudogene, and the MER67Bdup, that replicates the exon4_10 region downstream of the normal IKBKG gene. Using quantitative DNA analysis and microsatellite mapping, we established that both variants might promote the generation of the pathological IKBKGdel. Indeed, in family IP-516, the exon4_10 deletion was repositioned in the same allele from the pseudogene to the gene, whereas in family IP-688, the MER67Bdup generated the pathological IKBKGdel by recombination between two direct nonadjacent MER67Bs. Moreover, we found an instance of somatic recombination in a MER67Bdup variant, creating the IKBKGdel in an IP male. Our data suggest that the IP locus undergoes recombination producing recurrent variants that might be "at risk" of generating de novo IKBKGdel by NAHR during either meiotic or mitotic division.

An exploratory study of predisposing genetic factors for DiGeorge/velocardiofacial syndrome

“…Genetic variations in pseudogene sequences located at LCRs have been already proposed as rearrangement promoters57. We observed that, in DGS/VCFS parents-of-origin, the presence of a possible AK129567 pseudogene sequence was less frequent than in the general population.…”

Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology

“…The most common genetic mutation in IP is an approximately 11.7-kb deletion in the IKBKG gene that removes exons 4 through 10. This mutation accounts for 70–80% of patients with IP worldwide ( 22 – 24 ). This is found in European ( 25 – 27 ), Chinese ( 24 , 28 ), Japanese ( 29 – 31 ), Korean ( 32 , 33 ), and Indian ( 34 ) populations ( Supplementary Table 1 ).…”

Cognitive-behavioural phenotype in a group of girls from 1.2 to 12 years old with the Incontinentia Pigmenti syndrome: Recommendations for clinical management

“…IKBKG/NEMO codes for a regulatory subunit of NF-kB signalling, which is involved in many physiological functions such as immune and inflammatory responses, developmental processes, cell growth and apoptosis . Most IP patients have a recurrent deletion (termed NEMOΔ4-10) that generates, by recombination between two MER67B repeats located in introns 3 and 10 of the gene, and eliminates exons 4-10 of the gene, consequently abolishing the protein function Fusco et al, 2009;Fusco et al, 2012) (see Figure 1). In addition, small mutations (ins-del or missense) or an extended IKBKG/NEMO deletion have been reported in IP patients.…”

“…Incontinentia Pigmenti (IP, OMIM#308300), also known as Bloch-Sulzberger Syndrome, is an X-linked dominant multi-system genomic disorder, generally associated with a skewed X-chromosome inactivation in the blood cells (Fusco et al, 2009;Landy & Donnai, 1993). The occurrence of IP is estimated at about 1,393 female cases in the period 1993-2012 (Minic, Trpinac, & Obradovic, 2013).…”