The Rare and Atypical DIAbetes NeTwork (RADIANT) is a multicenter prospective cohort study that is dedicated to characterizing (discovering and defining) rare and atypical forms of diabetes. Individuals will be screened for evaluation of suspected atypical diabetes of unknown origin. Among the pool of evaluated individuals, those found to have a known form of diabetes will be excluded from further study. The remaining participants will be prioritized for genetic/genomic analysis and further testing.

RADIANT has three distinct stages.

Stage 1:

Stage 1 participants will complete a consent form and a questionnaire to determine the potential for having atypical forms of diabetes. Participants identified as potentially having atypical forms of diabetes based on questionnaire responses will be asked to provide a blood sample to test for islet autoantibodies and complete additional questionnaires.

The RADIANT Adjudication Committee, which is comprised of a team of experts in diabetes, will assess the data collected in Stage 1 and select and prioritize participants to proceed to Stage 2 and 3 for Whole Genome Sequencing (WGS) and other testing.

Stage 2:

Stage 2 of the study includes genetic screening for known forms of monogenic diabetes. Participants will consent for this stage of the study, complete a family history questionnaire, and have blood collected for DNA and RNA extraction, storage, and analysis. Whole genome sequencing (WGS) will be performed on all DNA samples. If WGS does not identify a pathogenic/likely pathogenic variant in a known monogenic diabetes gene that is thought to explain the participant's diabetes, RNA Sequencing will be performed at Baylor College of Medicine.

Stage 3:

Stage 3 of the study includes deeper phenotyping. All participants who proceed to Stage 3 will visit a study clinic to consent and complete Stage 3 procedures which include: an Oral Glucose Tolerance Test (OGTT), additional blood collection, a detailed physical exam, and additional questionnaires.

Discovery Team Review:

The work of the Discovery Team is expected to be an iterative process analyzing all data collected up to this point in the study to understand the significance of novel variants. In some instances, the Discovery Team may determine that enrollment of the Proband's family members is necessary. Family members with suspected atypical diabetes will follow the same study procedures as described above. Affected and unaffected family members may also be enrolled for Sanger Sequencing or trio WGS. The Discovery Team may also recommend additional optional procedures to better characterize the participant's form of diabetes.

The objective of this study is to define new forms of diabetes and the unique mechanisms underlying these forms of atypical diabetes. The specific aims are to:

• Identify and enroll individuals and families with undiagnosed rare and atypical forms of diabetes.
• Determine the etiologic basis of the metabolic disorder among individuals and families with novel forms of rare and atypical diabetes.
• Understand the pathophysiology of individuals and families with novel forms of rare and atypical forms of diabetes.

Primary Outcome Measures:

Phenotypic and genotypic characterization of previously unknown forms of diabetes using Whole Genome Sequencing (WGS), and deeper phenotyping methods [Time frame: Through study completion, an average of 3 years].

Deeper phenotyping methods include both clinical and laboratory assessments. Clinical data includes anthropometric and biometric data, medical histories, and questionnaires (ASA24, PROMIS, environmental exposures, depression and anxiety). Laboratory data includes WGS, RNA sequencing, Sanger sequencing, transcriptomics, metabolomics, mitochondrial sequencing, Oral Glucose Tolerance Test (OGTT), and Islet autoantibodies. Clustering methods will be used to define cohorts of similar diabetes genotypes and phenotypes based on the data.

Inclusion criteria:

The following criteria or phenotypes will be considered for suspecting "atypical" participants:

• Type 2 diabetes diagnosed at a time when the individual was pre-pubertal or non-obese
• Mendelian pattern, especially with early onset (< 18 years old)
• Syndromic (multiple systems involved)
• Lipodystrophic
• Extremes of BMI
• "Mitochondrial" characteristics (e.g., myopathy, hearing deficits)
• Non-progressive
• Rapidly progressive ("fulminant")
• Low insulin requirements (< 0.5 u/kg/day)
• Cyclical hyperglycemia with periods of remission
• Lean persons with polycystic ovarian syndrome (PCOS)
• History of gestational diabetes (GDM) when lean
• Lean insulin-resistant persons
• If islet autoantibodies and beta-cell function parameters have been measured (where "A" = islet cell autoantibodies, "B" = beta-cell function):
• A-B- (i.e., lacking islet autoimmunity makers and lacking beta cell function)
• A-B+ with unprovoked DKA at initial presentation (i.e., lacking islet autoimmune markers, with preserved beta-cell function, but presenting with unprovoked DKA)
• A-B+ of very young onset (pre-pubertal) (i.e., lacking islet autoimmune markers, with preserved beta-cell function, but very early onset T2D-like phenotype)

Exclusion criteria:

• Those with high likelihood of typical type 1, typical type 2, known monogenic, or other known secondary forms of diabetes
• Refusal of consent for genetic testing
• Islet autoantibody positive (participants who are islet autoantibody positive but present with additional atypical features (i.e., syndromic, strong linear family history of diabetes) may not be excluded)
• Women who are currently pregnant

The study is ongoing.