Genotype-first approach reveals monogenic lipodystrophy is underdiagnosed, with health and mortality risks

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.

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.

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.

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.

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).