Abstract
Congenital hypothyroidism is a severe metabolic disorder that is present at birth due to insufficient production of thyroid hormones. If not addressed early, it can lead to permanent growth delays and intellectual disabilities. One of the major genetic causes of congenital hypothyroidism is dyshormonogenesis, which disrupts the hormone synthesis pathway. The thyroid peroxidase (TPO) gene is crucial as it provides the enzyme needed for thyroid hormone synthesis within the thyroid gland. TPO catalyzes important steps in the iodination and coupling reactions in the thyroid. When this gene is mutated, enzyme activity is compromised, resulting in varying degrees of hypothyroidism. This article compiles information on TPO gene mutations associated with congenital hypothyroidism in Pakistani families. In Pakistan, consanguineous marriages are common, leading to a higher prevalence of inherited disorders, including congenital hypothyroidism. The mutations in the TPO gene identified to date range from missense mutations, which are single amino acid substitutions, to larger deletions of exons and issues at splice sites. This diversity reflects the variety of mutations present within local populations. In families affected by congenital hypothyroidism, the mutational load primarily stems from changes occurring in exons 8, 9, 10, 11, and 14. Molecular diagnostic tools, including next-generation sequencing and Sanger sequencing, are used to detect these mutations. Early genetic diagnosis followed by hormone replacement therapy, typically with levothyroxine, is effective in preventing developmental delays when administered promptly. Genetic testing and counselling can be instrumental in prevention efforts.