Abstract
BackgroundHuman Phenotype Ontology (HPO) has risen as a useful tool for precision medicine by providing a standardized vocabulary of phenotypic abnormalities to describe presentations of human pathologies; however, there have been relatively few reports combining whole genome sequencing (WGS) and HPO, especially in the context of structural variants.MethodsWe illustrate an integrative analysis of WGS and HPO using an extended pedigree, which involves Prader–Willi Syndrome (PWS), hereditary hemochromatosis (HH), and dysautonomia-like symptoms. A comprehensive WGS pipeline was used to ensure reliable detection of genomic variants. Beyond variant filtering, we pursued phenotypic prioritization of candidate genes using Phenolyzer.ResultsRegarding PWS, WGS confirmed a 5.5 Mb de novo deletion of the parental allele at 15q11.2 to 15q13.1. Phenolyzer successfully returned the diagnosis of PWS, and pinpointed clinically relevant genes in the deletion. Further, Phenolyzer revealed how each of the genes is linked with the phenotypes represented by HPO terms. For HH, WGS identified a known disease variant (p.C282Y) in HFE of an affected female. Analysis of HPO terms alone fails to provide a correct diagnosis, but Phenolyzer successfully revealed the phenotype-genotype relationship using a disease-centric approach. Finally, Phenolyzer also revealed the complexity behind dysautonomia-like symptoms, and seven variants that might be associated with the phenotypes were identified by manual filtering based on a dominant inheritance model.ConclusionsThe integration of WGS and HPO can inform comprehensive molecular diagnosis for patients, eliminate false positives and reveal novel insights into undiagnosed diseases. Due to extreme heterogeneity and insufficient knowledge of human diseases, it is also important that phenotypic and genomic data are standardized and shared simultaneously.
Highlights
Human Phenotype Ontology (HPO) has risen as a useful tool for precision medicine by providing a standardized vocabulary of phenotypic abnormalities to describe presentations of human pathologies; there have been relatively few reports combining whole genome sequencing (WGS) and HPO, especially in the context of structural variants
Clinical presentation and family history Here, we present the phenotypic characterization of a Utah pedigree K10031, consisting of 14 individuals from three generations (Fig. 1) with various medical
In contrast to studies that have searched for the “causal” gene, some have reported that genetic variations can instead have large effects on phenotypic variability, suggesting underlying genomic complexity from multiple interacting loci [91,92,93,94]
Summary
Human Phenotype Ontology (HPO) has risen as a useful tool for precision medicine by providing a standardized vocabulary of phenotypic abnormalities to describe presentations of human pathologies; there have been relatively few reports combining whole genome sequencing (WGS) and HPO, especially in the context of structural variants. Many studies have used whole exome sequencing (WES) to facilitate the molecular diagnosis of individuals with diseases that appear to have a single large-effect size mutation contributing substantially to the development of the disease, referred to by many as “Mendelian disorders” [14, 15]. Such disorders have an extraordinary phenotypic variability and spectrum brought about by genetic background, environmental differences and stochastic developmental variation (SDV) [16,17,18,19,20]
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