A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda

Rare diseases pose significant diagnostic and management challenges. In Ayurveda, these conditions are not explicitly mentioned (referred as Anukta Vyadhi) and are interpreted using foundational principles of Dosha imbalance with a systems perspective. This study examines the potential of the Anukta Vyadhi framework to deconvolute rare diseases. Human Phenotype Ontology (HPO), comprising 10,610 phenotypic terms across 12,678 rare diseases, was used to create a unifying vocabulary for mapping with Ayurvedic classifications. 140 Nanatamja Vikara (NV) based phenotypic descriptions that map to imbalance of specific Dosha Vata (80 nV), Pitta (40 nP) and Kapha (20 nK) curated from classical Ayurveda texts were mapped to HPO phenotypes. An extensive exercise was undertaken to preserve the meaning and context of Sanskrit descriptions while mapping HPO phenotypes and applying the structured principles of the Anukta Vyadhi framework. Rare diseases were re-annotated with nV, nP, and nK-labeled phenotypes and reinterpreted through this lens. The framework was further applied to three exemplary rare diseases—Steinert Myotonic Dystrophy (108 HPO terms), Syndromic Diarrhea (52 HPO terms), and Alstrom Syndrome (117 HPO terms)—to demonstrate its utility. Of the total NVs (140), 92% (128) mapped to 199 HPO IDs which corresponded to 7,200 rare diseases. Among these, 66% were uniquely enriched in nV associated phenotypes, followed by nP (6.5%) and nK (3.3%). Approximately 18% of diseases exhibited dual NV involvement, while 5% had contributions from all three Dosha. Seizures, short stature, and ptosis were predominant features of nV; gastroesophageal reflux, fever, and abnormal skin blistering of nP; and obesity, lethargy, and pallor were dominant of nK. Detailed case interpretations revealed that Steinert Myotonic Dystrophy (SMD) was primarily associated with Vata and secondarily with Kapha, Syndromic Diarrhea (SD) with Vata-Pitta involvement, and Alstrom Syndrome (ALMS) with contributions from all three doshas.This Anukta Vyadhi framework provides an innovative approach for interpreting rare diseases through foundational principles of Dosha . Integration of this framework with HPO provides (a) an assistive tool for rare disease diagnostics in Ayurveda clinics and (b) opens avenues of redefining rare diseases from systems perspective and (c) palliative management through complementary therapies.