GENETIC BASIS OF CONGENITAL ADRENAL HYPERPLASIA IN PAKISTANI POPULATIONS

Abstract

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders primarily caused by mutations in the CYP21A2 gene, leading to 21-hydroxylase deficiency and impaired cortisol synthesis. This study aimed to explore the genetic mutations underlying CAH and their correlation with clinical phenotypes in a Pakistani cohort. A total of 60 patients (38 females and 22 males) with a mean age of 7.4 years were included, and genetic analysis was performed using Sanger sequencing and MLPA. The study revealed a high consanguinity rate (76.7%), which significantly contributes to the inheritance of autosomal recessive disorders. Clinically, 56.7% of patients presented with the salt-wasting form of CAH, 33.3% with simple virilizing, and 10% with non-classic types. Genetic analysis demonstrated a heterogeneous mutation spectrum, with gene conversions (33.3%) and point mutations (30%) being the most common, followed by large deletions (25%) and small indels (11.7%). A strong genotype-phenotype correlation was observed; null mutations such as Null/Null and Null/I2G were predominantly associated with salt-wasting CAH, while milder variants like V281L were linked to non-classic presentations. These findings not only align with global mutation trends but also suggest unique mutational signatures in the Pakistani population, likely influenced by genetic isolation and high intra-community marriage rates. The study emphasizes the utility of molecular diagnostics in early detection, precise classification, and personalized treatment planning for CAH. It also highlights the importance of integrating genetic counseling and newborn screening into public health strategies to reduce diagnostic delays and improve disease management in resource-constrained environments. Overall, this research enhances the understanding of CAH’s genetic architecture in Pakistan and provides a foundation for future studies and policy interventions.