Avani Dave, Jai Hind College
Hirschsprung disease (HSCR) is a congenital condition in which intestinal neurons in the distal portion of the intestine are missing. This complicated hereditary disorder causes sickness by a combination of numerous abnormalities in the DNA.
A unique mix of genetic changes, including uncommon coding variations, predisposing haplotypes, and Copy Number Variation (CNV), can explain the genesis of HSCR (CNV). The Copy Number Variants (CNVs) are vast regions of our genome that are duplicated or deleted and are one of these variations. Hirschsprung disease is frequently seen in patients who have no other symptoms. A small percentage of individuals, however, have additional anatomical abnormalities and neurological problems. Additional anatomical abnormalities or neurological problems affect around 18% of individuals (HSCR-AAM). Because several genes are typically impacted by a CNV, identifying the actual culprits can be difficult.
The course of the study:
A recent study conducted by Kuil, L. E., et al. used a zebrafish model, to look at how this loss of characteristic genes impact enteric neuron growth in vivo. The researchers chose candidate genes based on gene enrichment methods and subjected them to further analysis. The patients in this investigation were divided into three groups:
- HSCR-AAM with associated abnormalities,
- HSCR patients with no associated abnormalities, and
- HSCR patients with coding mutations in disease-related genes (HSCR-isolated).
All HSCR patients with a verified pathogenic rare coding variation were placed in the third category. These patient groups were compared to unaffected controls by the researchers. Predisposing haplotypes were discovered, showing that each HSCR subgroup had increasing contributions of predisposing haplotypes, with the largest contribution in isolated HSCR individuals lacking RET coding mutations.
HSCR-AAM patients showed higher Copy Number (CN) losses, according to CNV profiling. Gene enrichment methods and constraint metrics were utilized to find probable candidate genes inside CN losses using mouse enteric nervous system transcriptomes. They also discovered in vivo epistasis between decreased Ret and Gnl1 expression and reduced Ret and Tubb5 expression. In HSCR-AAM patients, rare significant CN losses—often de novo—contribute to HSCR. The findings showed that six genes are involved in the development of the enteric nervous system and Hirschsprung disease. It was further observed that CNVs in individuals with concomitant abnormalities are more commonly bigger than in unaffected controls or Hirschsprung patients without additional symptoms.
Revelations:
To summarise, HSCR genetics is complicated, with predisposing haplotypes playing a role in all HSCR subgroups. In HSCR-AAM individuals, rare big CNVs—often de novo contribute significantly to the illness. These CNVs are particularly rich in CN losses and Enteric nervous system genes (ENS), which are also constrained coding regions (CCRs).
Disruption of these genes in zebrafish revealed decreased expression of several of these genes, alone or in conjunction with enhanced incidence of ENS changes. UFD1L gene is involved in signaling receptor binding, and MAPK8 gene is involved in axon guidance, therefore these genes have functional overlap with known HSCR illness genes.
The “ENS gene”-based strategy utilized during this study resulted in the discovery of additional HSCR candidate genes. This demands a more detailed and intricate analysis to unfold the mechanistic pathways followed in HSCR patients.
Also read: RCoNet: Diagnosing COVID-19 using chest X-rays
Reference:
- Kuil, L. E., MacKenzie, K. C., Tang, C. S., Windster, J. D., Le, T. L., Karim, A., de Graaf, B. M., van der Helm, R., van Bever, Y., Sloots, C. E. J., Meeussen, C., Tibboel, D., de Klein, A., Wijnen, R. M. H., Amiel, J., Lyonnet, S., Garcia-Barcelo, M.-M., Tam, P. K. H., Alves, M. M., … Brosens, E. (2021). Size matters: Large copy number losses in Hirschsprung disease patients reveal genes involved in enteric nervous system development. PLOS Genetics, 17(8), e1009698. https://doi.org/10.1371/journal.pgen.1009698
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Author info:
Avani Dave is currently in the final year of her bachelor’s degree, majoring in Life Sciences. Holding a good academic and extra-curricular record, she is on a constant journey of acquiring exposure in her field of interest while simultaneously not limiting herself to just that. Avani likes studying Diseases and Syndromes and everything under this umbrella! That being said, she is adept at working across departments and promises to deliver.
LinkedIn – https://www.linkedin.com/avani-dave/
Publications in BioXone:
- (2021). Lymphoblastic lymphoma in two young siblings – Case study. BioXone. https://bioxone.in/news/worldnews/lymphoblastic-lymphoma-in-two-young-siblings-case-study/
- Dave, A. (2021). Reduced levels of CD99 on Leukocytes without chromosome Y. BioXone. https://bioxone.in/news/worldnews/reduced-levels-of-cd99-on-leukocytes-without-chromosome-y/
- Dave, A. (2021). Indulgence of dominant primates in vocal communication! BioXone. https://bioxone.in/news/worldnews/indulgence-of-dominant-primates-in-vocal-communication/
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