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. 2025 Aug;197(8):e64067.
doi: 10.1002/ajmg.a.64067. Epub 2025 Apr 3.

Human Phenotype Ontology Annotations for Rare Congenital Conditions: Application to Arthrogryposis Multiplex Congenita

Shahrzad Nematollahi  1   2 , Reggie C Hamdy  3   4 , Harold van Bosse  5 , Joyce Li  3 , Daniel Blanshay-Goldberg  3 , Johanna I P de Vries  6 , Klaus Dieterich  7 , Isabel Filges  8 , Tanya Bedard  9 , Melissa Haendel  10 , Monica Munoz Torres  10 , Peter N Robinson  11 , Noémi Dahan-Oliel  1   2
Affiliations

Human Phenotype Ontology Annotations for Rare Congenital Conditions: Application to Arthrogryposis Multiplex Congenita

Shahrzad Nematollahi et al. Am J Med Genet A. 2025 Aug.

Abstract

Arthrogryposis multiplex congenita (AMC) represents a large, rare group of congenital conditions. This study addressed major challenges in AMC research posed by the lack of systematic frameworks for data collection and the use of inconsistent terminologies and text descriptions. We aimed to systematically review the Human Phenotype Ontology (HPO) terms, encode AMC phenotypic traits as HPO terms, and pilot test the encoding process in a cohort of children with AMC. An international consensus-based dataset for AMC was used to extract phenotypic traits from the fetal period to adulthood. The encoding process was developed by an international expert panel to expand and revise HPO ontology for joint contractures, as the main characterizing traits in AMC. Using a pre-tested mapping algorithm, the HPO mapping process resulted in a 62% complete match, a 12% incomplete match, and a 26% no match. The encoding process included 37 new terms and annotations and 13 re-structures across 10 different joints. The implemented annotations significantly increased the number of available HPO terms for joint contractures in a cohort of children with AMC (p-value = 0.04). Our encoding and annotation approach may be used as a blueprint for systematic HPO (re)annotations for musculoskeletal and non-musculoskeletal phenotypic traits of AMC.

Keywords: arthrogryposis multiplex congenita; diagnostic support; human phenotype ontology; ontology; patient matching; rare diseases; registries.

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Conflict of interest statement

Conflict of interest disclosure:

The authors have stated that they had no interests, which might be perceived as posing a conflict or bias.

Figures

Figure 1-
Figure 1-
Study design: A, Flowchart of the study phases. B, The re-annotation process for joint contractures’ ontology included: 1) extraction of annotations and terms describing joint contractures in AMC; 2) validation of terms by the study expert panel; 3) discussion and approval of the suggestions by the HPO expert panel. Abbreviations:†Common data elements;‡Arthrogryposis multiplex congenita;§Human Phenotype Ontology.
Figure 2-
Figure 2-
Revision and expansion of Human Phenotype Ontology (HPO) for joint contractures ontology. A, Schematic representation of the restructuring of HPO tree. Main branches of HPO where restructuring was performed are marked with light green. B, Shoulder contracture as an example of the encoding process. New additions and suggestions are marked with green, and repositioned terms are marked with yellow.
Figure 3-
Figure 3-
Images depicting flexion contracture: (A)10-year-old male with flexion contracture in wrist joint, thumb, and fingers; (B) 9-year-old male with bilateral knee flexion contracture (i.e., lack of knee extension).
Figure 4-
Figure 4-
Images depicting extension contracture: (A) 15-year-old male with maximum range of motion at the hip of 15 degrees flexion, demonstrating a hip extension contracture; (B) 10-year-old female with maximum range of motion of 10–15 degrees of flexion at the knees, demonstrating an extension contracture of the knees.
Figure 5-
Figure 5-
5-year-old male with forearm pronation contracture.
Figure 6-
Figure 6-
Images depicting ulnar deviation of the hand: (A) 9-year-old male with bilateral ulnar deviated wrists; (B) 7-months-old female with ulnar deviated wrist.
Figure 7-
Figure 7-
Left hand and wrist radial deviation in a 11-year-old female.
Figure 8-
Figure 8-
Images depicting external rotation contracture: (A) Bilateral hip external rotation contracture in an 8-month-old male; (B) One-year-old male with hip flexion, abduction and external rotation contractures. Knees have bilateral extension contractures and equinovarus of the feet. Other contractures include shoulder internal rotation and elbow flexion contractures (60).
Figure 9-
Figure 9-
Images depicting adduction contracture: (A) 5-year-old male with adducted thumb on right hand; (B) 6-year-old female with bilateral foot adduction contracture.
Figure 10-
Figure 10-
9-year-old male with hip abduction contracture.
Figure 11-
Figure 11-
Image depicting plantar flexion contracture in a 6-year-old female.
Figure 12-
Figure 12-
Metatarsus adductus in a 6-month-old female with clubfoot.
Figure 13-
Figure 13-
Comparison of available Human Phenotype Ontology (HPO) terms per person before and after the encoding process (*p-value=0.04).
See this image and copyright information in PMC

References

    1. Dahan-Oliel N, Cachecho S, Barnes D, Bedard T, Davison AM, Dieterich K, et al. International multidisciplinary collaboration toward an annotated definition of arthrogryposis multiplex congenita. Am J Med Genet C Semin Med Genet. 2019;181(3):288–99.doi: 10.1002/ajmg.c.31721. Epub 2019 Jul 7. - DOI - PMC - PubMed
    1. Lowry RB, Sibbald B, Bedard T, Hall JG. Prevalence of multiple congenital contractures including arthrogryposis multiplex congenita in Alberta, Canada, and a strategy for classification and coding. Birth Defects Res A Clin Mol Teratol. 2010;88(12):1057–61. doi: 10.02/bdra.20738. Epub 2010 Nov 15. - DOI - PubMed
    1. Dieterich K, LeTanno P, Kimber E, Jouk PS, Hall J, Giampietro P. The diagnostic workup in a patient with AMC: overview of the clinical evaluation and paraclinical analyses with review of the literature. Am J Med Genet C Semin Med Genet. 2019;181:337–44. doi: 10.1002/ajmg.c.31730. Epub 2019 Aug 1. - DOI - PubMed
    1. Hunter JM, Kiefer J, Balak CD, Jooma S, Ahearn ME, Hall JG, et al. Review of X-linked syndromes with arthrogryposis or early contractures-aid to diagnosis and pathway identification. Am J Med Genet A. 2015;167A:931–73. doi: 10.1002/ajmg.a.36934. Epub 2015 Mar 19. - DOI - PubMed
    1. Hall JG. Arthrogryposis (multiple congenital contractures): Diagnostic approach to etiology, classification, genetics, and general principles. European Journal of Medical Genetics. 2014;57(8):464–72. doi: 10.1016/j.ejmg.2014.03.008. Epub Apr 3. - DOI - PubMed