The monogenic forms of obesity in Saudi families.
5 affiliations
- 1Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University,, P.O. Box 2460, Riyadh 11451, Saudi Arabia.
- 2Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia.
- 3King Faisal Specialist Hospital Research Centre, Riyadh, 13458, Saudi Arabia.
- 4King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia.
- 5Hevolution Foundation, King Saud University, Riyadh 13519, Saudi Arabia.
Abstract
Background
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.'Objectives
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.Methods
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.Results
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.Conclusion
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.
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BibTeX
@article{almolafikh2026monogenic,
title = {{The monogenic forms of obesity in Saudi families.}},
author = {Sultanah Turki Almolafikh and Ali A Alshatwi and Razan Orfali and Haya AlSaud},
journal = {Human molecular genetics},
year = {2026},
month = oct,
doi = {10.1093/hmg/ddag054},
url = {https://europepmc.org/article/MED/42896087},
note = {CC BY},
}
RIS
TY - JOUR
TI - The monogenic forms of obesity in Saudi families.
AU - Sultanah Turki Almolafikh
AU - Ali A Alshatwi
AU - Razan Orfali
AU - Haya AlSaud
PY - 2026
DA - 2026/10/01
JO - Human molecular genetics
DO - 10.1093/hmg/ddag054
UR - https://europepmc.org/article/MED/42896087
AB - Background 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.'Objectives 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.Methods 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.Results 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.Conclusion 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.
SN - 0964-6906
SN - 1460-2083
ER -