The Human Phenotype Ontology: A Tool for Annotating and Analyzing Human Hereditary Disease

Robinson, Peter N.; Köhler, Sebastian; Bauer, Sebastian; Seelow, Dominik; Horn, Denise; Mundlos, Stefan

doi:10.1016/j.ajhg.2008.09.017

Cited by 850 publications

(790 citation statements)

References 27 publications

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“…However, no other genes associated with hereditary cardiomyopathy were observed to have rare variants in the sequenced individuals, and indeed, none of the genes with rare variants were associated with any kind of heart phenotype upon analysis with the Human Phenotype Ontology. 16 Recently, an important role for truncating mutations of TTN has been demonstrated for DCM, but rare missense mutations were common in groups of DCM patients as well as in controls. 1 Our results suggest that TTN missense mutations may be modifiers of clinical course in familial DCM in the presence of a mutation in another gene associated with DCM.…”

Section: Discussionmentioning

confidence: 99%

“…Only 28 such variants were found. Annotation data from the Human Phenotype Ontology project 16 were used to filter these variants and the associated genes, revealing eight genes in which variation has been associated with human Mendelian disease (Supplementary Table S5 and Supplementary Material). Only two these genes were found to be associated with abnormalities in the cardiovascular system, LMNA (lamin A/C) and TTN (titin), both of which are known to be associated with familial DCM.…”

Section: Targeted Wesmentioning

confidence: 99%

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Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

et al. 2013

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Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/ TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM. With the exception of TTN, truncating mutations of which have been found in up to 27% of individuals with DCM, 1 a single DCM-causing gene accounts for no more than 6-8% of all cases. The known DCM disease genes include those encoding for proteins of the sarcomere, the Z-disk, the cytoskeleton, the mitochondria, RNA binding proteins, the sarcoplasmic reticulum, and the nuclear envelope. 2-4 Familial DCM exhibits a remarkable degree of clinical variability with respect to severity, penetrance, and age of onset. 5 Like familial hypertrophic cardiomyopathy (HCM), familial DCM is often characterized by incomplete penetrance, a high degree of variable expressivity even among

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Section: Discussionmentioning

confidence: 99%

Section: Targeted Wesmentioning

confidence: 99%

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

et al. 2013

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“…Interestingly, the inclusion of disease phenotype similarities can substantially improve the performance of candidate gene prediction methods [21][22][23][24] . Resources like the Human Phenotype Ontology 25 (HPO) and the Mammalian Phenotype Ontology 26 provide a standardized vocabulary of phenotypic information that can also be used to transfer detailed knowledge of model organisms to interpret and predict associated phenomena in human 27,28 .…”

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confidence: 99%

Human symptoms–disease network

Zhou¹,

Menche²,

Barabási³

et al. 2014

Nat Commun

597

484

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In the post-genomic era, the elucidation of the relationship between the molecular origins of diseases and their resulting phenotypes is a crucial task for medical research. Here, we use a large-scale biomedical literature database to construct a symptom-based human disease network and investigate the connection between clinical manifestations of diseases and their underlying molecular interactions. We find that the symptom-based similarity of two diseases correlates strongly with the number of shared genetic associations and the extent to which their associated proteins interact. Moreover, the diversity of the clinical manifestations of a disease can be related to the connectivity patterns of the underlying protein interaction network. The comprehensive, high-quality map of disease-symptom relations can further be used as a resource helping to address important questions in the field of systems medicine, for example, the identification of unexpected associations between diseases, disease etiology research or drug design.

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“…Apache cTAKES also identifies the context in which the concepts are mentioned in the sentence including negation, patient history, family history, and uncertainty. The identified UMLS concepts were mapped to concept definitions in 20 clinical terminologies (Figure 1) including ICD‐9/10 (http://www.icd9data.com, http://www.icd10data.com), MeSH (Rogers, 1963), SNOMED CT (Schulz & Klein, 2008), and the Human Phenotype Ontology (Robinson et al, 2008). …”

Section: Methodsmentioning

confidence: 99%

Phelan‐McDermid syndrome data network: Integrating patient reported outcomes with clinical notes and curated genetic reports

Kothari

Wack

Hassen‐Khodja

et al. 2017

American J of Med Genetics Pt B

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The heterogeneity of patient phenotype data are an impediment to the research into the origins and progression of neuropsychiatric disorders. This difficulty is compounded in the case of rare disorders such as Phelan‐McDermid Syndrome (PMS) by the paucity of patient clinical data. PMS is a rare syndromic genetic cause of autism and intellectual deficiency. In this paper, we describe the Phelan‐McDermid Syndrome Data Network (PMS_DN), a platform that facilitates research into phenotype–genotype correlation and progression of PMS by: a) integrating knowledge of patient phenotypes extracted from Patient Reported Outcomes (PRO) data and clinical notes—two heterogeneous, underutilized sources of knowledge about patient phenotypes—with curated genetic information from the same patient cohort and b) making this integrated knowledge, along with a suite of statistical tools, available free of charge to authorized investigators on a Web portal https://pmsdn.hms.harvard.edu. PMS_DN is a Patient Centric Outcomes Research Initiative (PCORI) where patients and their families are involved in all aspects of the management of patient data in driving research into PMS. To foster collaborative research, PMS_DN also makes patient aggregates from this knowledge available to authorized investigators using distributed research networks such as the PCORnet PopMedNet. PMS_DN is hosted on a scalable cloud based environment and complies with all patient data privacy regulations. As of October 31, 2016, PMS_DN integrates high‐quality knowledge extracted from the clinical notes of 112 patients and curated genetic reports of 176 patients with preprocessed PRO data from 415 patients.

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The Human Phenotype Ontology: A Tool for Annotating and Analyzing Human Hereditary Disease

Cited by 850 publications

References 27 publications

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Human symptoms–disease network

Phelan‐McDermid syndrome data network: Integrating patient reported outcomes with clinical notes and curated genetic reports

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