Whole-Exome Sequencing Identifies Pathogenic Variants in SMPD1, HIP1R, and POMC Associated with Obesity in a Consanguineous Pakistani Population

Background and Objective: Obesity, defined as a Body Mass Index (BMI) ≥30 kg/m², is a multifactorial metabolic disorder arising from an imbalance between energy intake and expenditure. This study aimed to identify pathogenic variants in consanguineous Pakistani families with early-onset obesity to elucidate the genetic basis of the disorder. Materials and Methods: Twenty affected families and twenty sporadic obese individuals from various regions of Balochistan were recruited. Genomic DNA was extracted from peripheral blood, followed by whole-exome sequencing and validation using Sanger sequencing. Identified variants were analyzed using bioinformatics tools to predict their pathogenicity. Results: A heterozygous missense variant in the SMPD1 gene, segregating with autosomal dominant obesity, and previously reported variants in HIP1R and POMC genes associated with non-syndromic obesity phenotypes were identified. Conclusion: These findings broaden the mutational landscape of obesity-related genes, support genotype-phenotype correlations, and highlight the importance of genetic screening in consanguineous families for early diagnosis, counselling, and better understanding of hereditary obesity.