Kalim Alvin Santoso, Budi Nova Yuli Prasetyo, Hafiq Hamzah Muhammad, Maharani Annisa, Febrianti Maharani, Ryantono Fiko, Yulianda Dicky, Iskandar Kristy, Veltman Joris A
Pediatric Surgery Division, Department of Surgery/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia.
Department of Child Health/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/UGM Academic Hospital, Yogyakarta, Indonesia.
Front Pediatr. 2020 Mar 11;8:60. doi: 10.3389/fped.2020.00060. eCollection 2020.
The () gene has been implicated in the pathogenesis of Hirschsprung disease (HSCR), a complex genetic disorder characterized by the loss of ganglion cells in varying lengths of gastrointestinal tract. We wished to investigate the role of variants, both rare and common variants, as well as its mRNA expression in Indonesian HSCR patients. Sanger sequencing was performed in 54 HSCR patients to find a pathogenic variant in . Next, we determined expression in 18 HSCR patients and 13 anorectal malformation colons as controls by quantitative real-time polymerase chain reaction (qPCR). No rare variant was found in the S gene, except one common variant in exon 17, p.Lys701Gln (rs7800072). The risk allele (C) frequency at rs7800072 among HSCR patients (23%) was similar to those reported for the 1,000 Genomes (27%) and ExAC (28%) East Asian ancestry controls ( = 0.49 and 0.41, respectively). A significant difference in expression was observed between groups ( = 0.04). Furthermore, qPCR revealed that expression was strongly up-regulated (5.5-fold) in the ganglionic colon of HSCR patients compared to control colon (ΔC 10.8 ± 2.1 vs. 13.3 ± 3.9; = 0.025). We report the first study of aberrant expressions in HSCR patients and suggest further understanding into the contribution of aberrant expression in the development of HSCR. In addition, this study is the first comprehensive analysis of variants in the Asian ancestry.
（）基因与先天性巨结肠病（HSCR）的发病机制有关，HSCR是一种复杂的遗传性疾病，其特征是不同长度的胃肠道中神经节细胞缺失。我们希望研究该基因的罕见和常见变异体的作用，以及其在印度尼西亚HSCR患者中的mRNA表达。对54例HSCR患者进行桑格测序，以寻找该基因的致病变异。接下来，我们通过定量实时聚合酶链反应（qPCR）测定了18例HSCR患者和13例肛门直肠畸形结肠作为对照的该基因表达。在该基因中未发现罕见变异，仅在外显子17中发现一个常见变异，p.Lys701Gln（rs7800072）。HSCR患者中rs7800072的风险等位基因（C）频率（23%）与1000基因组计划（27%）和ExAC（28%）东亚血统对照中报告的频率相似（分别为 = 0.49和0.41）。两组之间观察到该基因表达存在显著差异（ = 0.04）。此外，qPCR显示，与对照结肠相比，HSCR患者神经节结肠中该基因表达强烈上调（5.5倍）（ΔC 10.8 ± 2.1对13.3 ± 3.9； = 0.025）。我们报告了第一项关于HSCR患者异常该基因表达的研究，并建议进一步了解异常该基因表达在HSCR发展中的作用。此外，本研究是对亚洲血统该基因变异的首次综合分析。
