Recent improvements in genetic analysis have considerably aided in gradually narrowing the obesity heritability gap and bringing to light monogenic variations that alter melanocortin signaling. In prior research, next-generation sequencing indicated a monogenic etiology in ∼50% of children with severe obesity from a consanguineous population in Pakistan. For a study, researchers sought to determine uncommon variations in obesity-causing genes in young individuals with severe obesity from the same area. 

Genomic DNA from 126 randomly chosen young adult obese participants (BMI 37.2±0.3 kg/m2; age 18.4±0.3 years) was analyzed for point mutations and copy number variations using standard or enhanced whole-exome analysis (CNVs). In addition, ELISA was used to assess leptin, insulin, and cortisol levels. 

They found 13 people with pathogenic or possibly pathogenic mutations in LEPR, PCSK1, MC4R, NTRK2, POMC, SH2B1, and SIM1. They also discovered two homozygous stop-gain mutations in the ASNSD1 and IFI16 genes in humans for the first time. Furthermore, they described nine homozygous mutations (seven missense, one stop-gain, and one stop-loss) and four copy-loss CNVs in genes or genomic areas previously associated with obesity-related phenotypes by genome-wide association studies. Pathogenic mutations in LEP and LEPR were either nonexistent or infrequent in this cohort of young adults, in contrast to obese children.