| Title: | Genotype-first approach reveals monogenic lipodystrophy is underdiagnosed, with health and mortality risks |
| Journal: | EBioMedicine |
| Published: | 18 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42001615/ |
| DOI: | https://doi.org/10.1016/j.ebiom.2026.106255 |
| URL: | https://www.thelancet.com/pdfs/journals/ebiom/PIIS2352-3964(26)00137-4.pdf |
Publication 17948
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Abstract
BACKGROUND: Monogenic lipodystrophy is a metabolic disorder that predisposes to diabetes and cardiovascular disease, yet its true prevalence and clinical spectrum remain uncertain. We used a genotype-first approach with an aim to estimate the prevalence, phenotypic spectrum, risk of cardiometabolic disorders and all-cause mortality associated with monogenic lipodystrophy in the population. We also assessed how these clinically unselected cases differ from clinically identified cases.</p>
METHODS: We analysed whole-genome sequencing data from 490,414 UK Biobank participants to identify pathogenic variants in 23 lipodystrophy genes. Individuals carrying a pathogenic genotype were compared with non-carriers for anthropometric traits, metabolic biomarkers, cardiometabolic outcomes, and all-cause mortality. We also compared UK Biobank cases with a clinically identified cohort of 58 individuals with monogenic lipodystrophy.</p>
FINDINGS: We identified 31 carriers of pathogenic monogenic lipodystrophy variants, giving a prevalence of 1 in 15,820 (95% CI: 1 in 23,282-1 in 11,145). Variants in PPARG and LMNA were most frequent, and prevalence did not differ by sex (P = 0.37). Compared with non-carriers, carriers had similar BMI but lower total body fat percentage (24.7% vs. 31.4%, P = 1.25 × 10-5), higher waist-hip ratio adjusted for BMI (0.91 vs. 0.87, P = 0.0044), elevated triglycerides (2.9 vs. 1.7 mmol/L, P = 6.69 × 10-5), and reduced HDL cholesterol (0.99 vs. 1.45 mmol/L, P = 6.26 × 10-9). These features were similar between men and women. None of the carriers had a diagnosis of lipodystrophy in electronic health records. Carriers had increased risk of diabetes (Adjusted HR 4.41, 95% CI 2.5-7.76), coronary artery disease (Adjusted HR 2.97, 95% CI 1.42-6.24), and heart failure (Adjusted HR 5.28, 95% CI 2.52-11.07). They also had almost fourfold higher mortality (Adjusted HR 4.02, 95% CI 2.16-7.48) over a mean follow-up of 13.6 years. Compared with clinically identified cases, UK Biobank carriers had milder phenotypes.</p>
INTERPRETATION: Monogenic lipodystrophy is more common than currently recognised and most cases remain undiagnosed despite significant cardiometabolic and mortality risks. These findings highlight the value of genotype-first approaches in studying lipodystrophy and support the need for earlier recognition and treatment in clinical practice.</p>
FUNDING: This work is funded by Diabetes UK (19/0005994 and 21/0006335), the MRC (MR/T00200X/1) and the Wellcome Trust (219606/Z/19/Z).</p>
8 Authors
- Luke N. Sharp
- Kevin Colclough
- Jacques Murray Leech
- Amy V. Evans
- Andrew T. Hattersley
- Michael N. Weedon
- Rebecca J. Brown
- Kashyap A. Patel
1 Application
| Application ID | Title |
|---|---|
| 103356 | Understanding the role of rare and common genetic variation in human phenotypes |
Enabling scientific discoveries that improve human health