Exome sequencing identifies novel genes and variants in patients with Hirschsprung disease.

Autor: Gunadi; Pediatric Surgery Division, Department of Surgery/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia. Electronic address: drgunadi@ugm.ac.id., Kalim AS; Pediatric Surgery Division, Department of Surgery/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia., Iskandar K; Department of Child Health/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/UGM Academic Hospital, Yogyakarta, Indonesia., Marcellus; Pediatric Surgery Division, Department of Surgery/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia., Puspitarani DA; Pediatric Surgery Division, Department of Surgery/Genetics Working Group, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia., Diposarosa R; Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Universitas Padjadjaran/Dr. Hasan Sadikin Hospital, Bandung, Indonesia., Makhmudi 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., Astuti GDN; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands/Division of Human Genetics, Center for Biomedical Research, Faculty of Medicine, Diponegoro University Semarang, Indonesia.
Jazyk: angličtina
Zdroj: Journal of pediatric surgery [J Pediatr Surg] 2023 Apr; Vol. 58 (4), pp. 723-728. Date of Electronic Publication: 2022 Nov 25.
DOI: 10.1016/j.jpedsurg.2022.11.011
Abstrakt: Background: 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.
Methods: 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%).
Results: 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.
Conclusions: 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 of Evidence: Level III.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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