Poster PresentationThe availability of new methodologies of high performance has revolutionized
our ability to discovery. However, the high resolution of such technologies
can become a double-edged sword. Reduced sample sizes available in
rare diseases are often an obstacle for the detection of candidate genes or
the study of their molecular basis. The limitations of the approaches based
on isolated genes can be overcome using systems biology approaches.
This study shows as a combination of pathway-based analysis (PBA) and
network analysis allowed to discover four new loci (RASGEF1A and IQGAP2,
DLC1 CHRNA7) related to signalling and migration processes associated
with the disease, which were then validated in a cohort of 106 independent
trios.
The further study of an international cohort of 162 HSCR trios allowed us
to confirm the molecular bases of disease using PBA. We found a significant
association of processes related to signalling and its regulation as well as
formation of the enteric nervous system. Although the genes associated
with HSCR varied in different populations, the functions and interaction of
affected networks of proteins were always the same, which reflects the complexity
of the disease. This methodology of prioritization of candidate genes
can be extrapolated to any technology of high performance (WES, RNA-seq,
etc.)