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Abstract

Abstract Background Inborn errors of metabolism (IEM) cause substantial neonatal morbidity and mortality. India’s large birth cohort, genetic diversity, and consanguinity in some communities heighten risk, yet expanded newborn screening (NBS) remains fragmented. This multicentre prospective cohort study evaluates integrated omics-based expanded NBS combining Liquid chromatography-tandem mass spectrometry (LC–MS/MS) metabolomics with targeted next-generation sequencing (NGS) for early IEM detection. Methods At least 10,000 neonates born at or admitted to Neonatal Intensive Care Units across nine centres will be recruited over 30 months. Dried blood spots collected at 48–72 hours of life will undergo first-tier LC–MS/MS quantification of amino acids and acylcarnitines, targeting aminoacidopathies, organic acidaemias, and fatty acid oxidation disorders. Abnormal profiles will trigger second-tier targeted NGS for confirmatory variant analysis. Confirmed cases will receive structured clinical evaluation, condition-specific treatment, and longitudinal follow-up to assess outcomes. Results The study will produce India’s first multicentre, population-level estimates of IEM birth prevalence across diverse geographic and genetic settings. Diagnostic performance—sensitivity, specificity, and positive and negative predictive values—will be evaluated for the integrated algorithm. Second-tier NGS is expected to reduce false-positive recalls substantially compared with metabolomics alone, while offering preliminary evidence on clinical benefits of early treatment. Conclusions This protocol establishes a reproducible and scalable evidence base for expanding newborn screening for IEM within India's public health system, and provides a structured framework to inform the development of a National Newborn Screening Programme for inherited metabolic disorders.