Examples /

Real cases in which Endeavour was used to prioritize disease candidate genes.

Case one

 KIF1A associated with hereditary spastic paraparesis.

This example is extracted from a paper by Erlich et al. [1]. The authors have studied a familial case of Hereditary Spastic Paraparesis (HSP) and were able to define a list of candidate genes through exome sequencing and homozygosity mapping. Then, their hypothesis was that one of these candidate genes must be associated with HSP, and therefore they have used several prioritization tools (including Endeavour) in order to identify the most likely candidate gene. Endeavour ranked KIF1A as the most likely candidate gene, and further functional elements (such as mutation analyses) were used to confirm that indeed it is responsible of the observed phenotypes. This example recreates the prioritization of KIF1A described in the paper. Endeavour is trained using the 11 genes that were associated to pure types of HSP at that time and all available human data sources. The candidate genes are 14 of the 15 candidate genes that were used in the original study (1 gene can not be found; uncharacterised locus). The results indicate that indeed KIF1A is the most probable disease causing gene.

[1] Erlich et al., Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis, Genome Res. (2011).

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Case two

 TAB2 associated with congenital heart defects.

his example is based on a paper by Thienpont et al. [2]. In this paper, we describe how we identified a region on chromosome 6 associated with cardiac defects through a genotype-phenotype correlation analysis. This region on 6q24-q25 region was further prioritized using Endeavour and several gene sets that represent different cardiac phenotypes or cardiac developmental processes. This reveals TAB2 as the top-ranked gene, and its role in cardiac development was further supported by expression analyses in human and model organisms, as well as knockdown experiments in zebrafish. Furthermore, a mutation analysis revealed two missense mutations and a balanced translocation, therefore demonstrating the role of TAB2 in cardiac development. This example recreates one of the prioritization described in the paper. Endeavour is trained using the 33 genes that were associated with congenital heart defects at the time of the study, and once again all available human data sources. The candidate genes are the 103 genes from the region 6q24-q25. The results indicate that TAB2 is the most probable disease causing gene.

[2] Thienpont et al., Haploinsufficiency of TAB2 causes congenital heart defects in humans, Am. J. Hum. Genet. (2010)

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