The monogenic forms of obesity in Saudi families

Obesity is a multifactorial disorder with a substantial yet incompletely defined genetic component. Rare monogenic variants, particularly in consanguineous populations, may account for part of the 'missing heritability.'

To delineate the genetic contribution to severe obesity in individuals from Saudi Arabia by pinpointing known and novel monogenic variants in families presenting with extreme phenotypes.

Eight multiplex Saudi families (each comprising 9 members; range: lean body weight to severe obesity) were enrolled. Adults had a BMI of ≥30 kg/m2; children exceeded the 90th percentile (overweight) or the 97th percentile (obese). Whole-exome sequencing (WES) was performed on samples collected from two children in each family, including one child with obesity and one control child without obesity. Variant calling files were filtered for quality, frequency < 1%, and predicted functional impact. Candidate loci were prioritized using Moon (Diploid) software and manual curation, then validated by Sanger sequencing.

Initial filtering revealed 40 rare, potentially pathogenic variants in 35 genes shared among affected relatives. Prioritization highlighted 28 variants in 19 candidate genes, encompassing established obesity-related genes (e.g. LEPR, MC4R, BDNF) and putative novel loci linked to appetite regulation, lipid metabolism, and energy balance. Segregation analysis identified both heterozygous and homozygous variants across affected individuals, reflecting variability in inheritance patterns. Seven previously reported candidate genes did not show pathogenic variants in this cohort. Carriers of prioritized variants exhibited significantly higher BMI z-scores than non-carriers (P < 0.01), underscoring a clear genotype-phenotype correlation.

This study broadens the catalog of genes associated with obesity in the Saudi population and demonstrates the value of studying extreme phenotypes in consanguineous families. Both previously recognized and novel variants were identified in association with severe, early-onset obesity, reflecting genetic heterogeneity across families rather than a single underlying mechanism. These findings provide a foundation for improved genetic characterization, tailored counseling, and future functional studies.