2123-LB: Discovery of CERS2 Haploinsufficiency Causing Atypical Lipodystrophy and Severe Fatty Liver Disease—Utility of Multiomics Analyses in the RADIANT study

Introduction and Objective: The RADIANT study, supported by NIDDK, seeks to uncover rare and atypical diabetes forms. Here we describe the use of multi-omic platforms to establish CERS2 haploinsufficiency as the etiology for monogenic diabetes with lipodystrophy in a RADIANT participant Methods: The proband is currently a 47-year-old female exhibiting a phenotype of atypical familial partial lipodystrophy with severe hypertriglyceridemia, metabolic dysfunction-associated steatohepatitis (MASH), insulin resistant diabetes, progressive neuropathy and premature CAD. Family history was positive for a similar presentation in her father. The father was also known to have a progressive neurological condition that ultimately led to development of neurogenic bladder and immobility, culminating in urosepsis and eventual death. Whole-genome and RNA sequencing, biochemical analysis and lipidomics were performed to elucidate the etiology of diabetes. Results: Whole-genome sequencing identified four nucleotide deletion variant (1:50941514ACAGG.A c.49_52delCCTG, pPro17Ter) in CERS2, a key gene in synthesizing very long-chain ceramides in the liver. The presence of the variant was confirmed by Sanger sequencing in proband and her deceased father. The CERS2 variant leads to anticipated nonsense-mediated decay (NMD), confirmed by RNA sequencing, which detected partial transcript depletion and skewed allele fractions. Biochemically, the patient had elevated C16 ceramides compared to higher chain ceramides. Comprehensive lipidomics revealed ceramide and sphingolipid profile similar to previously published haplo-insufficient mouse model data, and substantially different from simultaneously run controls. Conclusion: The clinical and molecular findings taken together with the biochemical and lipidomic phenotype provide sufficient evidence for the first documented human case of CERS2 haploinsufficiency, opening the door for development of precision therapies.