Novel Mutation-Deletion in the PHOX2B Gene of the Patient Diagnosed with Neuroblastoma, Hirschsprung’s Disease, and Congenital Central Hypoventilation Syndrome (NB-HSCR- CCHS) Cluster

Abstract

Introduction Neuroblastoma (NB), Hirschsprung disease (HSCR), Congenital Central Hypoventilation Syndrome (CCHS), clinically referred as the NB-HSCR-CCHS cluster, are genetic disorders linked to mutations in the PHOX2B gene on chromosome 4p12. Specific Aim The specific aim of this project is to define the PHOX2B gene mutations as the genomic basis for the clinical manifestations of the NB-HSCR-CCHS cluster. Patient A one day old male patient presented to the Jagiellonian University Medical College (JUMC), American Children Hospital, neonatal Intensive Care Unit (ICU) due to abdominal distention, vomiting, and severe apneic episodes. With the preliminary diagnosis of the NB-HSCR-CCHS, the blood and tissue samples were acquired from the child, as well as from the child’s parents. All procedures were pursued in accordance with the Declaration of Helsinki, with the patient’s Guardian Informed Consent and the approval from the Institutional Review Board. Genetic/Genomic Methods Karyotyping was analyzed based upon Giemsa banding. The patient’s genomic DNA was extracted from peripheral blood and amplified by polymerase chain reaction. Direct microfluidic Sanger sequencing was performed on the genomic DNA amplicons. These procedures were pursued in addition to the routine clinical examinations and tests. Results G-banding showed the normal 46 XY karyotype. However, genomic sequencing revealed a novel, heterozygous deletion (8 nucleotides: c.699–706, del8) in exon 3 of the PHOX2B gene on chromosome 4. This led to the frame-shift mutation and malfunctioning gene expression product. Conclusion Herein, we report a novel PHOX2B gene mutation in the patient diagnosed with the NB-HSCR-CCHS cluster. The resulting gene expression product may be a contributor to the clinical manifestations of these genetic disorders. It adds to the library of the mutations linked to this syndrome. Consequently, we suggest that screening for the PHOX2B mutations becomes an integral part of genetic counseling, genomic sequencing of fetal circulating nucleic acids and / or genomes of circulating fetal cells prenatally, while preparing supportive therapy upon delivery, as well as on neonates' genomes of intubated infants, when breathing difficulties occur upon extubation. Further, we hypothesize that PHOX2B may be considered as a potential target for gene therapy.

Pleiotropic effect of common PHOX2B variants in Hirschsprung disease and neuroblastoma

“…PHOX2B mutations in HSCR-NB cases suggest the gene has pleiotropic effects that influence sporadic cases of both HSCR and NB [20–22]. The association between a common PHOX2B variant (rs28647582) and HSCR risk has been investigated in case-control studies, but the results are inconsistent [23–26].…”

The Genetics of Sleep Disorders in Children: A Narrative Review

“…The discovery of the association between CCHS and the PHOX2B gene helped clinicians in the diagnostic work-up of the disorder. The screening for the PHOX2B mutations has been proposed as an integral part of genetic counselling and prenatal screening as well as a potential target for gene therapy [85].…”

Null mutation of the endothelin receptor type B gene causes embryonic death in the GK rat

“…The variation in phenotypes is attributed to the complex genetic interactions between discovered and unrevealed susceptibility loci or modifier loci in different genetic backgrounds, which regulate the development of ENS [3,5]. A series of genetic studies have already implicated several genes, including the RET proto-oncogene [7], the endothelin receptor type B gene ( EDNRB ) [8–10], the endothelin-3 gene ( EDN3 ) [11], the glial-cell-line-derived neurotrophic factor gene ( GDNF ) [12,13], the SRY-related HMG-box 10 gene ( SOX10 ) [14], the neurturin gene ( NRTN ) [15], the endothelin converting enzyme 1 gene ( ECE1 ) [16], the zinc finger homeobox 1B gene ( ZFHX1B ) [17], the paired-like homeobox 2B gene ( PHOX2B ) [18], the KIF1 binding protein gene ( KIF1BP ) [19], and the transcription factor 4 gene ( TCF4 ) [16]. Of these, the EDNRB gene, which is involved in the EDN3/EDNRB signaling, is known to play a key role in the development of HSCR, as either the heterozygous or homozygous mutation of this gene is found in HSCR patients [10,20,21].…”