First whole-genome sequencing analyses for rare bowel disease

10 October 2018

Fresh hope for more effective treatment strategies for Hirschsprung disease sufferers has emerged as a result of findings from the first whole-genome sequencing analyses on the disease by a research team from the Li Ka Shing Faculty of Medicine, University of Hong Kong (HKU).

While it was known that genetic defects could increase the chance of a child developing the disease, the study, co-led by Dr Elly Ngan Sau-wai (Croucher Fellowship 2000), revealed that disease risk is determined by different constellations of multiple DNA changes.

By using a human stem cell-based disease model, they also found that genes implicated in the Alzheimer’s disease pathway are dysregulated in a subgroup of Hirschsprung disease patients, suggesting these two diseases may share some common pathological mechanisms and drug targets. The research was published in Gastroenterology.

Hirschsprung disease (congenital megacolon) occurs globally but is particularly prevalent in Asia, affecting one in 3,000 babies. Those affected suffer from severe constipation and intestinal obstruction due to an absence of nerve cells that co-ordinate bowel movements.

In Hong Kong, more than 120 affected babies have undergone operations in the past 10 years to remove the portion of the bowel with no nerve cells. However, the outcome of surgery is variable and a significant number of patients still suffer from life-long complications, such as incontinence and short bowel syndrome.

In carrying out the research, the HKU team, led by Associate Professors Drs Ngan and Maria Mercedes Garcia-Barcelo, Department of Surgery, conducted whole-genome sequencing analyses of Hirschsprung disease sufferers recruited from hospitals in Hong Kong, mainland China and Vietnam. This involved 443 patients and 493 ethnically matched individuals without the disease (as controls).

From the analyses, four new Hirschsprung disease-associated sites on the genome were identified. The study revealed that changes in specific constellations of DNA in the regulatory and protein-coding regions of the genome provide a sensitised background that increases risk for the disease. By studying the cells generated from the stem cell-based Hirschsprung model, the team interconnected the DNA changes that increase the risk of disease with pathological pathways. In particular, dysregulation of an Alzheimer’s disease-associated pathway was found in a subgroup of Hirschsprung patients. Disruption of this pathway causes neuronal death, which may account for the lack of nerve cells in the colons of these patients.

The research, involving input from several other Croucher-associated researchers, builds on a decade of genetic and functional studies conducted by the team. This included the first whole-genome genetic screening of 200 Hirschsprung disease patients and 408 healthy individuals to identify the susceptibility genes for the disease, published in Proceedings of the National Academy of Sciences in 2009.

Drs Ngan and Garcia-Barcelo noted that greater understanding of the mechanisms underlying the disease creates an opportunity to establish a subtype-matched treatment strategy, enabling more precise, effective and affordable treatments for patients.  



Dr Elly Ngan received her BSc in Molecular Biology at the Hong Kong University of Science and Technology in 1995. She completed her PhD studies at the Department of Zoology, University of Hong Kong. In 2000 she was awarded a Croucher Fellowship to undertake postdoctoral research at Baylor College of Medicine, US, with a focus on transcription co-activators in human diseases. She is currently an Associate Professor in the Department of Surgery, University of Hong Kong. 


To view Dr Ngan’s Croucher profile, please click here