Morpho-Functional and Mutational Spectrum of Congenital Hypothyroidismin a Newborn Screening Cohort from Delhi

Congenital hypothyroidism (CH) is a leading preventable cause of intellectual disability, with a notably high incidence in India. However, data integrating its morphologic and genetic etiology in Indian cohorts remain scarce. Aim of this study was to characterize its etiology via thyroid imaging to assess TSH levels across morphological sub-types and genetic analysis in a subset of the CH cases with dyshormonogenesis. In this multicentric prospective study, approximately 200,000 newborns (≥34 weeks) recruited from across 20 hospitals in Delhi state underwent TSH screening via heel prick. CH was confirmed by venous testing and managed with levothyroxine and etiological evaluation included thyroid ultrasonography and technetium scintigraphy. Dyshormonogenesis was the most common etiology (62%), followed by thyroid dysgenesis. Athyreosis showed the highest TSH levels and dyshormonogenesis had significantly lower values (p< 0.001). Male neonates exhibited greater skeletal maturation delay. Whole exome sequencing revealed monogenic (n=17) and digenic (n=7) inheritance in 24/41 samples (58.53%) of the dyshormonogenesis cases, with known and novel variants in reported genes and TG was the most frequently mutated gene. Integrating genetic, phenotypic, and functional data may enhance our understanding of CH and guide precision care.