Copy Number Variations Due to Large Genomic Deletion in X-Linked Chronic Granulomatous Disease

Abstract

Mutations in genes for any of the six subunits of NADPH oxidase cause chronic granulomatous disease (CGD), but almost 2/3 of CGD cases are caused by mutations in the X-linked CYBB gene, also known as NAD (P) H oxidase 2. Approximately 260 patients with CGD have been reported in Japan, of whom 92 were shown to have mutations of the CYBB gene and 16 to have chromosomal deletions. However, there has been very little detailed analysis of the range of the deletion or close understanding of the disease based on this. We therefore analyzed genomic rearrangements in X-linked CGD using array comparative genomic hybridization analysis, revealing the extent and the types of the deletion genes. The subjects were five Japanese X-linked CGD patients estimated to have large base deletions of 1 kb or more in the CYBB gene (four male patients, one female patient) and the mothers of four of those patients. The five Japanese patients were found to range from a patient exhibiting deletions only of the CYBB gene to a female patient exhibiting an extensive DNA deletion and the DMD and CGD phenotype manifested. Of the other three patients, two exhibited CYBB, XK, and DYNLT3 gene deletions. The remaining patient exhibited both a deletion encompassing DNA subsequent to the CYBB region following intron 2 and the DYNLT3 gene and a complex copy number variation involving the insertion of an inverted duplication of a region from the centromere side of DYNLT3 into the deleted region.

Chronic granulomatous disease: Clinical, molecular, and therapeutic aspects

“…So far, large deletions and duplications are considered uncommon genetic mutation events in CGD patients, probably due to the difficulty to detect multiple exon deletions/insertions with conventional methods (sequencing, PCR-SSCP, Southern blot). Recently, array comparative genomic hybridization (array CGH) and multiplex ligationdependent probe amplification were proposed for the detection of copy number variations (26,27) in CGD patients also. Stasia et al (27) reported two interesting cases of male XR-CGD patients, one with a 5.7-kb duplication spanning exons 6 and 8 of CYBB gene and the other with a deletion of the same region.…”

Chronic granulomatous disease associated with Duchenne muscular dystrophy caused by Xp21.1 contiguous gene deletion syndrome: Case report and literature review

“…The RPGR deletion has been reported as one type of retinitis pigmentosa (Cehajic-Kapetanovic et al, 2020). The proximity of the RPGR genes and the CYBB gene makes it a common co-existing disorder (11/16) (El Nemer et al, 2000;Peng et al, 2007;Yamada et al, 2010;Arai et al, 2012;Al-Zadjali et al, 2015;Gassner et al, 2017;Lhomme et al, 2020). In our case, X-linked retinitis pigmentosa, conerod dystrophy, and primary ciliary dyskinesia secondary to the RPGR gene mutation may manifest later in life.…”

Reconstitución inmune exitosa mediante trasplante de células madre hematopoyéticas en un paciente colombiano afectado con enfermedad granulomatosa crónica

“…Aproximadamente, el 10 % de los pacientes con la enfermedad presentan grandes deleciones que afectan uno o más exones del gen, e incluso estas pueden abarcar genes contiguos como el XK (síndrome de McLeod), el OTC (transcarbamilasa de ornitina), el DMD (distrofia muscular de Duchenne) y el RP (retinitis pigmentosa), entre otros (23,24). En el presente estudio no se pudieron establecer los puntos de quiebre 5' y 3' de la deleción, por lo tanto, no fue posible establecer el rango de genes afectados, incluidos los ya mencionados.…”