Comprehensive Analysis of Patients with Undiagnosed Genetic Diseases Using the Patient Exploration Tools Suite (PETS)

Abstract

Systemic approaches based on network analysis have been successful in associating pathological phenotypes observed in patients with their affected genomic regions. Previously we have used phenotype-genotype associations to determine the genetic causes that lead to pathological phenotypes observed in patients with rare and complex disorders. However, these studies were limited as many of these associations had low specificity, frequently associating pathological phenotypes such as intellectual disability or growth abnormality with multiple regions of the genome. To help solve this problem, we propose that the phenotypic characterisation of patients using more specific terms will substantially improve the determination of the genetic causes that produce them. In this work we present the Patient Exploration Tools Suite (PETS), which includes three tools to: (1) determine the quality of information within a patient cohort; (2) associate genomic regions with their pathological phenotypes based on the cohort data; and (3) predict the possible genetic variants that cause the clinically observed pathological phenotypes using phenotype-genotype association values. This tool has been developed to be used by the clinical community, to facilitate patient characterisation, help identify where data quality can be improved within a cohort and help diagnose patients with complex disease.