ECEESPE2025 Poster Presentations MTEabolism, Nutrition and Obesity (125 abstracts)
Frequency of monogenic variants in a cohort of individuals with severe, early-onset obesity from a single large tertiary paediatric centre
Katherine Hawton1, 2, Hannah Hickingbotham3, Alanna Holt1, Sumana Chatterjee1, Julian Hamilton Shield1, 4 & Dinesh Giri1, 2
1University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom; 2University of Bristol, Bristol, United Kingdom; 3St George’s University Hospital NHS Foundation Trust, London, United Kingdom; 4NIHR Biomedical Research Centre Nutrition, Bristol, United Kingdom
JOINT3666
Introduction: Obesity is a complex, chronic disease characterised by excess adiposity which tracks throughout the lifecourse. Monogenic obesity presents in childhood with severe, early-onset obesity and hyperphagia, and its prevalence may be underestimated due to limited access to genetic testing. We describe genetic results from a large cohort of children and young people (CYP) living with severe obesity under the care of our tertiary paediatric weight management clinic.
Methods: 131 CYP with severe obesity (body mass index (BMI) >99.6th centile for age) had genetic testing performed using the Rare Obesity Advanced DiagnosisTM 79-gene targeted panel (including the MC4R pathway variants) between March 2022 and November 2024. Variants were classified as pathogenic or potentially relevant variants according to American College of Medical Genetics criteria; further subdivided into suspected pathogenic, variants of unknown significance and suspected benign.
Results: 69/131 patients were female. Age ranged from 1.5-17.5 years with onset of obesity between 3-11 years of age. Median BMI was 32.2kg/m2 (range 22.1-55.0) and median BMI-SDS was 3.72 (range 2.10-6.46). 9.2% (12/131) of CYP were found to have pathogenic variants and suspected pathogenic variants were found in 10.7% (14/131). 16.8% (22/131) had variants of unknown significance, 14.5% (19/131) had suspected benign variants (some CYP had more than one variant) and one had a deletion in the 16p11.2 chromosomal region. MC4R (heterozygous) was the most frequent pathogenic variant (3.8%; 5/131), followed by heterozygous SIM1 (3%; 4/131).
| Pathogenic Variants (frequency) | Potentially Relevant Variants (frequency) | Gene with polymorphic risk variant (frequency) | ||
| Suspected Pathogenic | Variant of Unknown Significance | Suspected Benign | ||
| MC4R heterozygous(5) SIM1 heterozygous(4) RAI1 heterozygous(1) VPS13B heterozygous(1) SEMA3G heterozygous(1) | KSR2(2) SEMA3A(2) TUB(2) BBS9(2) VPS13B(2) KIDINS220(1) | KIDINS220(2) PCSK1(2) SEMA3A(2) CREBBP(1) GNAS(1) KSR2(1) | ALMS1(3) NCOA1(3) KSR2(2) PCSK1(2) POMC(2) RAI1(2) | PCSK1 heterozygous (16) |
| Chromosomal rearrangement | BBS7(1) SEMA4 (1) | MAGEL2(1) PLXNA3(1) | EP300(1) HTR2C(1) | |
| 16p11.2 deletion(1) | TTC8(1) POMC(1) SDCCAG8(1) | RPS6KA3(1) DNMT3A(1) MC4R(1) PHF6(1) EP300(1) PCNT(1) IFT172(1) PLXNA1(1) MKKS(1) VPS13B(1) BBS5(1) CEP290(1) PLXNA4(1) TRIM32(1) BBIP1(1) | NRP1(1) SIM1(1) PLXNA2(1) BBS12(1) NROB2(1) |
Conclusion: In this clinical population of CYP living with severe obesity, almost 10% had pathogenic variants associated with obesity and a further 10% had suspected pathogenic variants. The majority of the above variants were in genes encoding proteins in the leptin-melanocortin pathway which is crucial in the regulation of appetite and energy expenditure. Increased provision of genetic testing may facilitate a deeper understanding of the monogenic causes of obesity and enable the development of further targeted, personalised therapies to improve long-term outcomes.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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