Identification of Associated Genes and Diseases in Patients With Congenital Upper Limb Anomalies

Purpose: Congenital upper limb anomalies (CULA) can present isolated or as a part of a syndrome or association. Therefore, surgeons dealing with CULA should be aware of associated diseases and anomalies. The newly accepted Oberg, Manske, and Tonkin (OMT) classification allows for registration of a wide spectrum of CULA. Therefore, providing associated diseases for each hand anomaly in the classification would aid differential diagnosis formulation in clinic and investigation of causal genes in research. The first aim of this study was to review the Human Phenotype Ontology (HPO) database for diseases and causative genes that can be related to hand anomalies present in the OMT classification. The second aim was to relate associated anomalies and inheritance patterns to improve differentiation between the diseases. Methods: The HPO database was reviewed for all diseases with a known causative gene related to hand anomalies. All hand phenotypes were classified according to the OMT classification; nonhand phenotypes were classified into anatomical groups. TIBCO Spotfire Software was used to visualize the contribution of each anatomical group to a given disease and to prioritize diseases based on this contribution. Results were compared with literature cases and to a current HPO tool, Phenomizer. Results: In total, 514 hand phenotypes were obtained, 384 could be classified in the OMT classification, and 1403 diseases could be related to the OMT classification. Differentiation between diseases is illustrated by examples. Comparison to recently published hand phenotypes reveals that all were present in our data set. Gene prioritization using our methodology was better than Phenomizer in 4/5 examples. Conclusions: We present an OMT-classification-based methodology to aid clinicians in differential diagnosis formulation in patients with CULA. Furthermore, we enable discrimination between the diseases by providing insight in the differences in disease presentation. Gene prioritization and visualization in the proposed system outperforms systems in current use.