Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology

Abstract

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.

Keywords: GA4GH Phenopacket; HPO; fetal pathology; human phenotype ontology; prenatal diagnosis; prenatal phenotyping.

FIGURE 1

Example attributes of the HPO disease annotation model (HPOA). (a) Schematic representation of our model of a rare disease. Associated with the diseases are a variety of features. (b) This schematic represents one HPO annotation for the disease dyserythropoietic anemia, congenital, type IV. Published phenotypes include anemia with infantile onset; all five of the patients with the disease presented this way (shown as f = 5/5). An annotation to a treatment (intrauterine fetal transfusion coded by a MAxO term) is shown; the treatment treats anemia, as well as nonimmune hydrops fetalis, a less frequent phenotypic manifestation of the disease.

FIGURE 2

Prenatal onset terms. The HPO provides terms to denote the range of onset of diseases or phenotypic features. New terms were added for more granularity in the prenatal period. Prenatal ages are shown as gestational weeks, which are defined as the time from the last menstrual period of the mother. For instance, embryonal onset refers to a disease or phenotypic feature that is first observed in the 8 weeks following fertilization, which corresponds to 10 weeks of gestation (WG). 13 WG + 6D refers to a gestational age of 13 weeks and 6 days.

FIGURE 3

Components of a Phenopacket. (a) The subject message provides basic demographic information; (b) The phenotypicFeatures message consists of a list of phenotypic features (each of which begins with “‐type” in YAML format as shown here). The patient was found to have Increased fetal lens echogenicity (HP:0034248) at a gestational age of 27 weeks, at which time Microphthalmia (HP:0000568) was excluded. Postnatal examination at an age of 4 days (represented in iso8601 format as P4D) shows Axial hypotonia (HP:0008936), Low‐set ears (HP:0000369), and Microphthalmia (HP:0000568). (c) The disease diagnosis is recorded using a term from the Mondo ontology (Shefchek et al., 2020), Warburg micro syndrome (MONDO:0016649). (d) The metaData message records versions of ontologies used to create the Phenopacket together with other information. Additionally, the Phenopacket schema provides resources to record measurements, biospecimens, and treatments, not shown here.