Pediatric Surgery Division, Department of Surgery/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia.
Pediatric Surgery Division, Department of Surgery/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia.
J Pediatr Surg. 2023 Apr;58(4):723-728. doi: 10.1016/j.jpedsurg.2022.11.011. Epub 2022 Nov 25.
Hirschsprung disease (HSCR) is a complex genetic disease characterized by the absence of ganglion cells in the intestines, leading to a functional obstruction in infants. At least 24 genes have been identified for the pathogenesis of HSCR. They contributed to approximately 72% of HSCR cases. We aimed to elucidate further the genetic basis of HSCR in Indonesia using the whole-exome sequencing (WES) approach.
WES was performed in 39 sporadic non-syndromic HSCR patients and 16 non-HSCR subjects as controls. Variants presented in controls were excluded, followed by in silico prediction tools and population allele frequency databases to select rare variants. We determined the minor allele frequency (MAF) using gnomAD (MAF <0.1%).
We involved 24 (61.5%) males and 15 (38.5%) females. Most patients (62%) had short-segment aganglionosis and underwent the Duhamel procedure (41%). We identified several candidate novel variants in HSCR-related genes, including UBR4, GDNF, and ECE1. Moreover, we also identified some novel candidate genes, including a possible compound heterozygous variant in the MUTYH gene: the first variant, a known protein-truncating variant associated with colorectal cancer (CRC), p.Glu452Ter and the second variant is novel, p.Ala39Val. Moreover, the type of variants was not associated with the aganglionosis type.
We identified several novel genes and variants, including the variant associated with CRC, that might contribute to the pathogenesis of HSCR. No genotype-phenotype associations were noted. Our study further confirms the complex network involved in enteric nervous system development and HSCR pathogenesis.
Level III.
先天性巨结肠（HSCR）是一种复杂的遗传疾病，其特征是肠内神经节细胞缺失，导致婴儿出现功能性肠梗阻。至少有 24 个基因已被确定与 HSCR 的发病机制有关。它们促成了大约 72%的 HSCR 病例。我们旨在使用全外显子组测序（WES）方法进一步阐明印度尼西亚 HSCR 的遗传基础。
对 39 例散发型非综合征性 HSCR 患者和 16 例非 HSCR 对照进行 WES。排除对照中出现的变异后，使用计算机预测工具和人群等位基因频率数据库选择罕见变异。我们使用 gnomAD（MAF<0.1%）确定了次要等位基因频率（MAF）。
我们纳入了 24 例（61.5%）男性和 15 例（38.5%）女性患者。大多数患者（62%）存在短节段无神经节细胞症，并接受了 Duhamel 手术（41%）。我们在 HSCR 相关基因中发现了几个候选的新变异，包括 UBR4、GDNF 和 ECE1。此外，我们还发现了一些新的候选基因，包括 MUTYH 基因的一种可能的复合杂合变异：第一个变异是一种与结直肠癌（CRC）相关的已知蛋白截断变异，p.Glu452Ter，第二个变异是新的，p.Ala39Val。此外，变异类型与无神经节细胞症类型无关。
我们发现了几个新的基因和变异，包括与 CRC 相关的变异，这些变异可能有助于 HSCR 的发病机制。未观察到基因型-表型相关性。我们的研究进一步证实了参与肠神经系统发育和 HSCR 发病机制的复杂网络。
III 级。
