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Oral Presentation - 40
Unraveling the Molecular Basis of Clinical Heterogeneity in Hirschsprung Disease through Gene Expression Analysis
Muntadhar M Isa 1, Maimun Syukri 2, ZA Muchlisin 3, . Gunadi 4, Dian Adi Syahputra 1, Teuku Yusriadi 1, Yumna Muzakkir 1, Reno Keumalazia Kamarlis 5, Zulham Effendy 6, Ahmad Setyadi 6, Siti Maghfirah 6, Tristia Rinanda 7
1 Pediatric Surgery Division, Surgery Department Faculty of Medicine Universitas Syiah Kuala/ Dr. Zainoel Abidin General Hospital, Banda Aceh, Indonesia
2 Division of Nephrology and Hypertension, Department of Internal Medicine Faculty of Medicine Universitas Syiah Kuala/ Dr. Zainoel Abidin General Hospital, Banda Aceh, Indonesia
3 Faculty of Marine and Fisheries, Universitas Syiah Kuala
4 Pediatric Surgery Division, Department of Surgery, Universitas Gajah Mada/dr. Sardjito Hospital, Yogyakarta, Indonesia
5 Department of Pathology Anatomy, Faculty of Medicine, Universitas Syiah Kuala/ Dr. Zainoel Abidin General Hospital, Banda Aceh, Indonesia
6 Department of Surgery, Universitas Syiah Kuala/Dr. Zainoel Abidin General Hospital, Banda Aceh, Indonesia
7 Microbiology Department, Syiah Kuala University, Banda Aceh, Indonesia
Background: Hirschsprung disease (HSCR) can increase morbidity and mortality in children because it causes a functional blockage. Data on the epidemiology and genetics of HSCR in the Acehnese ethnic group in Indonesia are still limited, despite a higher incidence rate in Aceh compared to national and global averages. We aimed to explore the association between RET, NRG1, SEMA3, and RarB genes and the phenotypes of HSCR patients, including sex, HSCR type, age at diagnosis, and complications, in the Acehnese ethnic group.
Methods: This study employs an observational analytical design with a cross-sectional approach. A total of 57 HSCR patients who underwent surgery at Dr. Zainoel Abidin Hospital in Aceh were included in the study. Demographic, clinical, and histopathological data were collected systematically. Both aganglionic and ganglionic tissues from the colon or rectum were sampled from HSCR patients, along with control samples from each patient with anorectal malformation. mRNA expression of RET, NRG1, SEMA3, and RarB genes was measured using real-time PCR, and statistical analysis was performed to assess the relationship between gene expression, genotypic profiles, and clinical phenotypes.
Results: Among the 57 patients, the majority were male (70.2%), and most had short-segment HSCR (98.2%). Clinical signs included abdominal distension (100%), delayed meconium passage (86%), and a positive squirt sign (77.2%). Treatments for HSCR included transanal endorectal (87.9%), transanal Swenson-like (38.6%), transabdominal Soave (1.8%), and Duhamel (1.8%) pull-throughs. The expression of NRG1 showed a significant decrease in aganglionic colon tissue compared to control colon (2.84-fold; p=0.02). The expression of RET showed a substantialdecrease in both aganglionik and ganglionic tissue (3.23-fold; p=0.02 and 3.89-fold, p=0.02, respectively). While SEMA and RarB showed variable expression. The expression of the SEMA3gene showed a significant decrease in aganglionic tissues (3.05-fold; p=0.03) and also in ganglionic tissues (2.94-fold, p=0.04) compared to the control colon. The expression of RARB also showed a significant decrease in agalionic tissues (3.14; p<0,01), and also ganglionic tissues (2.60-fold; p=0.03). The SEMA3 and RarB genes are significantly more expressed in female HSCR patients. The NRG1 is more highly expressed in male HSCR patients. Age significantly influences NRG1 gene expression, with the lowest levels observed in individuals under 1 year old. Significant associations were found between family history, HSCR type, and delayed diagnosis, as well as complications.
Conclusions: Our study indicates that RET, NRG1, SEMA3, and RarB expressions play a significant role in the development and influence the phenotype of HSCR patients within the Acehnese population. These findings further confirm the complexity of HSCR pathogenesis. Additionally, our study is the first to report RarB expression in patients with HSCR and their association with the phenotypes.