SAT080 Partnering With Medical Genetics To Provide Molecular Diagnosis In Atypical Diabetes
Authors: Foss de Freitas Maria Cristina , Chase Colby , Henry Marie-Louise , Neidert Adam , Narla Goutham , Uhlmann Wendy , Lee Kristen , Oral Elif A 
Published: October 2023

Disclosure: M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. C. Chase: None. M. Henry: None. A. Neidert: None. G. Narla: Advisory Board Member; Self; HERA Biolabs. Consulting Fee; Self; RAPPTA Therapeutics. Owner/Co-Owner; Self; RAPPTA Therapeutics. W. Uhlmann: None. K. Lee: None. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Novo Nordisk, Fractyl Laboratories, Rhythm Pharmaceuticals, GID Dynamics. Other; Self; Aegerion Pharmaceuticals.

Uncovering genetic alterations causing rare and atypical phenotypes related to diabetes mellitus is becoming increasingly possible with next-generation sequencing. Our Atypical Diabetes Program formed a partnership with the Division of Genetic Medicine, creating a specialized Atypical Diabetes Genetics Clinic to provide genetic counseling and clinical diagnostic testing to patients with rare forms of diabetes and other metabolic diseases. Between 10/2019 and 07/2022, 82 patients were seen (42±12 years old; 76.3% female). Indications for referral varied: 32 (39.0%) were referred for suspected monogenic obesity, 31 (37.8%) for familial partial lipodystrophy (FPLD), 10 (12.2%) for MODY, 7 (8.5%) for familial dyslipidemia (FD), 4 (4.9%) for acquired partial lipodystrophy (APL), and 14 (17.1%) for other indications including concern for acquired generalized or partial lipodystrophy, adrenomyeloneuropathy, Alport syndrome, GIST, hemochromatosis, hypothyroidism and hypogonadism, immune dysregulation, laminopathy, multisystem health problems/congenital anomalies, Prader-Willi syndrome, renal glycosuria, and TAR syndrome. Fourteen (17.1%) patients were referred for multiple indications. Results from 64 patients who underwent genetic testing revealed 4 positive molecular findings (all in patients with lipodystrophy), confirming a pathogenic LMNA variant detected on research testing in one and revealing previously unknown molecular etiologies in three (a previously described likely pathogenic LMNA variant, a novel likely pathogenic PPARG variant, and a previously described homozygous pathogenic MFN2 variant). Clinical management was altered, aiming for a more personalized approach in patients with these new findings, and two are participating in clinical trials for their condition. Cascade testing for family members is now being pursued. Sixteen patients had variants of uncertain significance (VUS); in one of these cases, in silico prediction suggesting that the detected SH2B variant could be pathogenic has enabled enrollment in a Phase 2 study with setmelanotide. For other identified VUS, we are undertaking functional and biological studies using our novel translational platform, which was established to contribute evidence for possible variant reclassification. Deeper sequencing strategies are being considered for patients with negative results, with most of our patients participating in an NIH funded network study for Rare and Atypical Diabetes (RADIANT). In our early experience, partnering with a medical genetics team to provide molecular testing for rare forms of diabetes and other metabolic conditions can lead to precise molecular diagnosis and set the stage for deeper testing and improved clinical care while driving novel discovery work.

Presentation: Saturday, June 17, 2023