Genetic and Functional Studies of Hirschsprung Disease

Hirschsprung disease (HSCR) is a heterogeneous, complex genetic disease involving mutations (in combination) in several genes. The differential contribution of rare and common coding and non-coding variants vary in accordance with gender and length of aganglionosis. Major mutations in genes involved in HSCR are also linked to ENS development, and defects in ENCCs migration, proliferation, differentiation and survival display HSCR like phenotype in animal models. Exome sequencing of families with unidentified mutations in known HSCR genes have led in identification of new HSCR genes. Mutations in regulatory elements encompassing the RET locus are associated with HSCR. Detailed epigenome profiling of different cell types and tissues by the Human epigenome atlas project have now provided desired datasets for interrogating the role of epigenetic marks in HSCR. Development of new transgenic models in model organisms such as, zebrafish has also facilitated the validation studies of genomic findings. All these studies identified a large number of genes and loci however they explain only part of the total genetic risk for HSCR.
In this thesis we aim at finding novel genes, mutation within these genes and ENS specific regulatory regions that could explain part of the missing heritability.