Inheritance-mode specific pathogenicity prioritization (ISPP) for human protein coding genes

• DOI: 10.1093/bioinformatics/btw381
• Publication Date: 2016-06-29T14:57:42Z
• Authors: Jacob Shujui Hsu; Johnny S.H. Kwan; Zhicheng Pan; Maria-Mercè Garci...; Pak Chung Sham; Miaoxin Li
• Keywords: Haploinsufficiency; Mendelian inheritance; Exome; Inheritance; Candidate gene

Abstract Motivation: Exome sequencing studies have facilitated the detection of causal genetic variants in yet-unsolved Mendelian diseases. However, identification disease genes among a list candidates an exome study is still not fully settled, and it often difficult to prioritize candidate for follow-up studies. The inheritance mode provides crucial information understanding diseases, but none existing gene prioritization tools utilize this information. Results: We examined characteristics under different modes. results suggest that with autosomal dominant (AD) are more haploinsufficiency de novo mutation sensitive, whereas those recessive (AR) significantly non-synonymous regulatory transcript isoforms. In addition, X-linked (XL) fewer synonymous variants. As result, we derived new scoring system prioritizing diseases according mode. Our assigned each annotated protein-coding (N = 18 859) three pathogenic scores (AD, AR XL). This mode-specific framework achieved higher accuracy (area curve 0.84) XL Conclusion: inheritance-mode specific pathogenicity (ISPP) outperformed other well-known methods including Haploinsufficiency, Recessive, Network centrality, Genic Intolerance, Gene Damage Index Constraint scores. systematic suggests manifesting modes tend unique characteristics. Availability implementation: ISPP included KGGSeq v1.0 (http://grass.cgs.hku.hk/limx/kggseq/), source code available from (https://github.com/jacobhsu35/ISPP.git). Contact: [e-mail] Supplementary information: data at Bioinformatics online.