Szymońska Izabela, Borgenvik Thore Langfeldt, Karlsvik Tina Margrethe, Halsen Anders, Malecki Bianka Kathryn, Saetre Sindre Ervik, Jagła Mateusz, Kruczek Piotr, Talowska Anna Madetko, Drabik Grażyna, Zasada Magdalena, Malecki Marek
Department of Pediatrics, Jagiellonian University Medical College, Krakow, Poland, EU.
Jagiellonian University Medical College, Krakow, Poland, EU.
J Genet Syndr Gene Ther. 2015 Dec;6(3). doi: 10.4172/2157-7412.1000269. Epub 2015 Sep 7.
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 gene on chromosome 4p12.
The specific aim of this project is to define the gene mutations as the genomic basis for the clinical manifestations of the NB-HSCR-CCHS cluster.
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.
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 gene on chromosome 4. This led to the frame-shift mutation and malfunctioning gene expression product.
Herein, we report a novel 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 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 may be considered as a potential target for gene therapy.
神经母细胞瘤（NB）、先天性巨结肠症（HSCR）、先天性中枢性低通气综合征（CCHS），临床上称为NB-HSCR-CCHS综合征群，是与4号染色体p12区域基因突变相关的遗传性疾病。
本项目的具体目标是确定该基因突变是NB-HSCR-CCHS综合征群临床表现的基因组基础。
一名1日龄男婴因腹胀、呕吐和严重呼吸暂停发作被送至雅盖隆大学医学院（JUMC）美国儿童医院新生儿重症监护病房（ICU）。初步诊断为NB-HSCR-CCHS综合征群后，采集了患儿及其父母的血液和组织样本。所有程序均按照《赫尔辛基宣言》进行，获得了患者监护人的知情同意，并得到了机构审查委员会的批准。
遗传/基因组学方法：基于吉姆萨染色分析核型。从外周血中提取患者的基因组DNA，并通过聚合酶链反应进行扩增。对基因组DNA扩增子进行直接微流控桑格测序。除了常规临床检查和检测外，还进行了这些操作。
G显带显示正常的46 XY核型。然而，基因组测序发现4号染色体上该基因的外显子3存在一个新的杂合缺失（8个核苷酸：c.699-706，del8）。这导致了移码突变和基因表达产物功能异常。
在此，我们报告了一例被诊断为NB-HSCR-CCHS综合征群患者的新基因突变。由此产生的基因表达产物可能是这些遗传性疾病临床表现的一个因素。它增加了与该综合征相关的突变文库。因此，我们建议在产前对胎儿循环核酸和/或循环胎儿细胞基因组进行基因组测序时，以及在分娩时准备支持性治疗时，对插管婴儿拔管后出现呼吸困难时对其基因组进行筛查时，将该基因的突变筛查作为遗传咨询的一个组成部分。此外，我们假设该基因可被视为基因治疗的潜在靶点。
