Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Hong Kong
The Netherlands
International Hirschsprung Disease Consortium

Project Coordinator

Inserm/ University of Paris V


Aravinda Chakravarti IRCCS - Instituto Giannina Gaslini Laboratorio di Genetica Molecolare Baltimore, USA
Isabella Ceccherini IRCCS - Instituto Giannina Gaslini Laboratorio di Genetica Molecolare Genova, Italy
Paul Kwong Hang Tam The University of Hong Kong Surgery Hong Kong, China
Robert Hofstra University Medical Center Groningen University of Groningen Groningen, The Netherlands
Salud Borrego Hospitales Universitarios Virgen del Rocio (HUVR) Unidad Clinica de Genética y Reproduccion Seville, Spain

Publications of the HSCR project

Major results of the project

Hirschsprung disease (HSCR, 1/5,000 live births) is characterized by the congenital absence of enteric neurons and ganglia ganglion cells in the hindgut, leading to intestinal obstruction. The length of aganglionosis is variable and correlates with the severity of the disease. Despite the high number of sporadic cases (80%), segregation analyses showed that HSCR is inherited as a complex sex-modified oligogenic trait with: i) a skewed sex-ratio (4/1); ii) an overall risk to siblings of 4% (relative risk l= 1/200), and iii) pedigrees (20% of cases) that suggest an incompletely penetrant major locus, now identified as the RET proto-oncogene. Despite these results, the molecular pathology at the RET locus, genes other than RET contributing to HSCR development, and the physiopathologic bases of this malformation remain unknown. To address these questions, an International HSCR Consortium for patients genotyping was established, with the participation of 6 groups working in 3 different continents: Baltimore (Aravinda Chakravarti); Paris (Stanislas Lyonnet); Genoa (Isabella Ceccherini); Groningen (Robert Hofstra ); Hong Kong (Paul Tam) and Seville (Salud Borrego). The collaborative effort allowed to assemble a large cohort of HSCR patients and their families, yielding a resource for the understanding of the genetic and molecular bases of such a complex disease. We have already collected and started to genotype 876 HSCR families (2,672 individuals) for 14 markers at the RET locus. Overall, a non coding enhancer mutation showed the highest transmission to affected sibs. The genetic distribution of that variant is consistent with the higher prevalence of HSCR in Chinese than in Caucasian populations. Moreover, HSCR risk was shown to vary by the patients’ length of aganglionosis, gender and presence of coding mutations. Following these preliminary studies, our goals are to: i) deepen the role of the RET gene in the molecular genetics of HSCR, ii) study the molecular bases and the complex genetic model behind the oligogenic predisposition to HSCR, and, thereby, iii) identify new genes involved in the development of the neural crests from which the entire enteric nervous system originates. programme.

Based on our genetics background, and especially on the work already started within the International HSCR Consortium, the present research programme addressed the following questions:
- To enlarge the spectrum of RET involvement in Hirschsprung disease (HSCR), through extensive mutations and polymorphisms screening and deletions search;
- to characterize the molecular processes underlying the association of the RET gene with different degrees of disease predisposition;
- to search for candidate genes in the chromosomal regions where RET modifier loci have been mapped or hypothesized (chromosomes 3p21, 9q,19q12, and 21);
- to look for additional HSCR genes by undertaking genome-wide association and linkage studies in the Consortium cohort of HSCR families;
- to search for other HSCR related genes, based both on their involvement in enteric nervous system development and on phenotypes presented by murine models;
- to work out a new genetic counselling protocol for HSCR by estimating the risk associated with the predisposing RET intron 1 SNP allele.

E-Rare 2012 - Created by Toussaint Biger