Search

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families., Methods: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis., Results: We identified 2 rare biallelic variants in CAPNS1 , encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH., Conclusion: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors.)

In childhood, a multitude of causes lead to pulmonary alveolar proteinosis (PAP), an excessive surfactant accumulation in the alveolar space, limiting gas exchange. Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) causing autoimmune PAP, the principal aetiology in adults, are rare. In this first case series on autoimmune PAP, we detail the presentation and management issues of four children. Whereas three children presented insidiously with progressive dyspnoea, one was acutely sick with suspected pneumonia. During management, one patient was hospitalised with coronavirus disease 2019, noninvasively ventilated, and recovered. All treatment modalities known from adults including whole-lung lavage, augmentation of GM-CSF by inhaled GM-CSF, removal of neutralising antibody by plasmapheresis and interruption of antibody production using rituximab were considered; however, not all options were available at all sites. Inhaled GM-CSF appeared to be a noninvasive and comfortable therapeutic approach. The management with best benefit-to-harm ratio in autoimmune PAP is unknown and specialised physicians must select the least invasive and most effective treatment. To collect this cohort in a rare condition became feasible as patients were submitted to an appropriate registry. To accelerate the authorisation of novel treatments for autoimmune PAP, competent authorities should grant an inclusion of adolescents into trials in adults., Competing Interests: Conflict of interest: M. Griese reports grants or contracts received from Böhringer Ingelheim paid to their institution; participation on a Data Safety Monitoring Board or Advisory Board for Böhringer Ingelheim, personal fees received. Unpaid Head chILD-EU; all disclosures made outside the submitted work. Conflict of interest: P. Panagiotou has nothing to disclose. Conflict of interest: E.D. Manali reports receiving grants or contracts, paid to their institution, from Hoffmann La Roche, Boehringer Ingelheim and Savara; personal payments for lectures, presentations, speakers' bureaus, manuscript writing or educational events received from Hoffmann La Roche and Boehringer Ingelheim; support for attending meetings and/or travel paid to the institution received from Hoffmann La Roche and Boehringer Ingelheim; all disclosures made outside the submitted work. Conflict of interest: M. Stahl has nothing to disclose. Conflict of interest: N. Schwerk has nothing to disclose. Conflict of interest: V. Costa has nothing to disclose. Conflict of interest: K. Douros has nothing to disclose. Conflict of interest: M. Kallieri has nothing to disclose. Conflict of interest: R.M. Urbantat has nothing to disclose. Conflict of interest: H. von Bernuth reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from CSL Behring and Octapharma; participation on an advisory board for Takeda; and is an associate member of the Standing committee on vaccinations. All disclosures made outside the submitted work. Conflict of interest: L. Kolilekas has nothing to disclose. Conflict of interest: L. Morais has nothing to disclose. Conflict of interest: A. Ramos has nothing to disclose. Conflict of interest: K. Landwehr has nothing to disclose. Conflict of interest: K. Knoflach has nothing to disclose. Conflict of interest: F. Gothe has nothing to disclose. Conflict of interest: K. Reiter has nothing to disclose. Conflict of interest: V. Papaevangelou has nothing to disclose. Conflict of interest: A.G. Kaditis has nothing to disclose. Conflict of interest: C. Kanaka-Gantenbein has nothing to disclose. Conflict of interest: S.A. Papiris reports receiving grants or contracts paid to their institution from Hoffmann La Roche, Boehringer Ingelheim and Savara; personal payments received from Hoffmann La Roche and Boehringer Ingelheim for attending meetings and/or travel; all disclosures made outside the submitted work., (Copyright ©The authors 2022.)

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)