Nuclear factor kappa B essential modulator (NEMO) deficiency syndrome is a rare X-linked recessive genetic disorder characterized by a wide range of clinical features, including increased susceptibility to bacterial and mycobacterial infections, as well as skin manifestations such as ectodermal dysplasia, dental abnormalities, hypospadias, and alopecia. The syndrome is caused by mutations in the IKBKG gene. Hypomorphic mutations in the IKBKG are associated with two clinically distinct conditions: hypohidrotic or anhidrotic ectodermal dysplasia with immunodeficiency and incontinentia pigmenti. These differences may result from the specific types and locations of the mutations, as well as the mosaic expression of IKBKG due to random X-chromosome inactivation in heterozygous females.
This case report describes a 2-month-old male who presented with a history of Enterobacter aerogenes and Klebsiella pneumonia infections, osteogenesis imperfecta, and erythematous skin lesions. The patient’s mother and sister exhibited symptoms consistent with incontinentia pigmenti. Genetic analysis was carried out by whole-exome sequencing (WES) using Exome Capture V5 Probe Set (MGI). WES was performed using a DNBSEQ-G50 genetic analyzer (MGI). Clinically significant observations were confirmed by Sanger sequencing.
Genetic analysis of the gDNA sample identified a heterozygous pathogenic variant in exon 10 of the IKBKG gene (NM_003639.4: c.1167dupC, p.Glu390ArgfsTer5). The presence of heterozygous variants in IKBKG gene, located on the X-chromosome in males, may be due to the presence of pseudogenes IKBKGP1. Long-range PCR (LR-PCR) was performed to confirm the presence of pathogenic mutation in the IKBKG gene. As expected, Sanger sequencing of the LR-PCR amplicon confirmed the pathogenic variant c.1167dupC in a hemizygous state.
We report the first genetically confirmed case of NEMO deficiency syndrome in Belarus. Our results demonstrate that heterozygous genetic variations in the IKBKG gene observed in boys may be caused by the presence of the IKBKGP1 pseudogene, and the approach to genetic diagnosis employed enables us to detect potential pathogenic variants and differentiate between them derived from IKBKG or its pseudogene.
