Monogenic Causes in the Type 1 Diabetes Genetics Consortium Cohort: Low Genetic Risk for Autoimmunity in Case...

Area of Science:

• Genetics
• Endocrinology
• Diabetes Research

Background:

• Approximately 1% of type 1 diabetes diagnoses are misidentified monogenic diabetes.
• Distinguishing between type 1 and monogenic diabetes is crucial for appropriate therapeutic management.
• Genetic testing is costly, necessitating effective patient selection strategies.

Purpose of the Study:

• To test the hypothesis that low genetic risk for type 1 diabetes can aid in selecting patients for monogenic diabetes testing.
• To evaluate the utility of genetic risk markers in identifying monogenic diabetes among autoantibody-negative individuals.

Main Methods:

• Exome sequencing was performed on families with multiple affected children from the Type 1 Diabetes Genetics Consortium (T1DGC).
• Families were selected based on the absence of two specific autoantibodies and protective human leukocyte antigen haplotypes.
• Analysis focused on identifying actionable monogenic variants within these selected families.

Main Results:

• Of 46 families meeting criteria, 7 (41.2%) with an affected parent and 14 (48.3%) without an affected parent harbored actionable monogenic variants.
• Five families without an affected parent had recessive WFS1 variants, indicating monogenic diabetes without typical Wolfram syndrome features.
• This targeted sequencing approach identified 55.8% of estimated monogenic diabetes cases within the T1DGC cohort, using only 11.1% of autoantibody-negative samples.

Conclusions:

• Low genetic risk markers for type 1 diabetes are effective for selecting patients for monogenic diabetes screening, even without a family history.
• Prospective screening studies utilizing autoimmunity markers are warranted.
• Nonsyndromic WFS1 variants are a frequent cause of monogenic diabetes misdiagnosed as type 1 diabetes.