Poster Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Copy number variations and rare genetic mutations associated with childhood obesity at a tertiary obesity management service (128509)

Jade L Clemens 1 2 , Rae-Chi Huang 1 2
  1. Perth Children's Hospital, Nedlands, WA, Australia
  2. Perth Children's Hospital Endocrinology Department, Healthy Weight Service, Nedlands, WA, Australia

Aims:

Childhood obesity is a worldwide issue. In Australia, 19.3% of children are overweight, and 8.3% are obese. Environmental and polygenic causes remain most common, however, monogenetic causes are significant in the pathogenesis of early onset severe obesity, Identifying monogenetic causes via screening may help tailor therapy.

 

We aimed to identify copy number variants (CNV)’s and monogenetic mutations associated with obesity at an Australian tertiary paediatric obesity service. and key factors predictive of a monogenetic cause in our population.

Methods:
We reviewed databases (January 2008-April 2025), excluding patients with common syndromic causes including Bardet-Beidl and Prader Willi Syndrome. Our site’s monogenetic obesity screen encompasses LEP, LEPR, POMC, GHRL, MC4R genes and whole exome sequencing (WES) for CNV’s. Data was grouped by age of obesity onset </≥5 years) and presence/absence of neurodevelopmental (intellectual, sensory or communication) delays. 

Results:

From 2980 records, we identified 43 variants in 39 individuals with abnormal microarray or WES. 100% of patients with monogenetic cause had early onset obesity (mean age 3.2± 3.3years) and neurodevelopmental differences (baseline population prevalence estimate=15.9%).  Mean % 95th percentile BMI was 151± 23%.

Chromosome 16p CNV’s were most common (25.6%). Ten (25.6%) were known pathogenic mutations, two (5.1%) were of unclear clinical significance.  Eighteen (46.2%) CNV’s of unclear clinical significance were identified. Four (15.4%) patients had rare syndromes associated with obesity. Four (10.3%) had pathogenic WES abnormalities. Seven (17.9%) had multiple genetic mutations.  Three had commenced GLP1-agonist therapy. 

 

Conclusions:

Consistent with international literature, mutations impacting the leptin-melanocortin pathway were the most common in our cohort. Rates of comorbid neurodevelopmental differences were higher than levels quoted in literature possibly reflecting tertiary centre population and selective testing. With enhanced accessibility to genetic testing, it is likely that rates of monogenic obesity in our cohort are underestimated.