Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data

Abstract

High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.

Healthy human aging: intrinsic and environmental factors

“…According to the authors of this paper, Census-based datasets of aged individuals with comprehensive phenotyping are invaluable resource toward the improved understanding of variant pathogenicity. A few recent publications which supported the above mentioned investigation is cited below (CHEN et al, 2016;DEWEY et al, 2015;FERNANDES et al, 2016;HENN et al, 2015;LEK et al, 2016).…”

Exome sequencing identifies de novo pathogenic variants in FBN1 and TRPS1 in a patient with a complex connective tissue phenotype

“…A summary of the exome-sequencing statistics for each family member is presented in Table 1. A tiered annotated output of all sequence variant calls in the patient is included in Supplemental Table 1, as given by the Sequence to Medical Phenotypes pipeline (Dewey et al 2015). Alignment and variant filtering identified two high-quality de novo pathogenic variants in disease genes related to the clinical phenotype (Table 2).…”

A primer to clinical genome sequencing

“…At a minimum annotation incorporates information about the presence of a variant within a gene and the predicted function of the variant upon the protein product of that gene (30). Many commonly used annotation tools offer a variety of other types of information about genetic variants such as describing the presence of the variant within human population databases, evolutionary conservation of the variant among different species, and aspects of local genomic structure where the variant is located (31). These data may then variously be incorporated into a clinical interpretation (Fig.…”