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Adipose Tissue_Appetite_and Obesity

SUN-671 - Integrative Genomics Reveals Molecular Drivers of Lipodystrophy in the RADIANT Study

Sunday, June 14, 2026
9:00 AM - 4:00 PM CT
Disclosure(s):
Elif A. Oral, MD: No relevant disclosure to display
Lipodystrophy syndromes are characterized by adipose tissue deficiency with heterogeneous etiologies; however, ~50% of familial partial lipodystrophy (FPLD) and most acquired forms lack defined molecular causes. The NIH-funded RADIANT network aims to identify genetic and mechanistic drivers of atypical diabetes syndromes. To date, we have evaluated 35 individuals with FPLD (M/F: 9/26, age range: 15-73 years) and 3 female individuals with acquired generalized lipodystrophy (AGL; ages 21, 55, and 63 years) through the RADIANT research pipeline.
Integrated analyses including whole genome sequencing, PBMC transcriptomics, and family segregation identified known pathogenic variants in established lipodystrophy genes (LMNA, PPARG) that were not recognized at the time of enrollment due to blended or atypical clinical presentations, resulting in delayed or missed diagnosis. Phenotypic expression was further modified by additional factors, including Turner syndrome, high polygenic type 1 diabetes risk, and monogenic obesity variants, highlighting multilayered genetic architecture. Overall, molecular leads were identified in all but one participant, with the findings presented here representing prioritized candidates.
In-depth investigation of one participant with FPLD identified a likely pathogenic truncating variant in CERS2, implicating sphingolipid metabolism in adipose dysfunction. Additional candidate variants (e.g., IRS2 p.Ser222Phe) demonstrated functional impact in Drosophila, with reduced fat body and overall body size, supporting a role in energy storage and growth. Ongoing modeling studies are evaluating SMAD5 and PTPMT1 variants identified in study participants. Variants prioritized for iPSC-based modeling include those in PLIN5, SRA1, UCP3, ADCY5, ISM1, and CD300LG, selected based on in silico prediction, family segregation, literature review, and biological plausibility.
Among the three participants with AGL, one individual harbored an LMNTD2 variant linked to the LMNA pathway. Two older participants developed acute-onset AGL following severe gastrointestinal stress, subsequently presenting with seronegative autoimmune hepatitis, severe hypertriglyceridemia, hepatomegaly, and refractory diabetes. Genomic analyses suggested combined metabolic and immune pathway perturbations without anti-perilipin antibodies, supporting a potential multi-hit model involving genetic susceptibility, metabolic stress, and immune dysregulation.
These findings demonstrate that integrative genomic and functional approaches can uncover molecular mechanisms underlying adipose tissue deficiency and diabetes, improve diagnostic precision in clinically ambiguous cases, and provide a framework for mechanism-based classification and future therapeutic targeting in lipodystrophy.

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