期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 106, 期 6, 页码 1804-1810出版社
ENDOCRINE SOC
DOI: 10.1210/clinem/dgab056
关键词
monogenic diabetes; type 1 diabetes; WFS1; HLA; autoantibody
资金
- Canadian Institutes of Health Research [PJT-159715]
It is hypothesized that about 1% of clinically diagnosed type 1 diabetes patients actually have non-autoimmune monogenic diabetes. By testing low genetic risk for type 1 diabetes, a significant percentage of patients with actionable monogenic variants can be identified, even in the absence of an affected parent. This approach could help in selecting patients for further screening studies and potentially change therapeutic strategies.
Hypothesis: About 1% of patients clinically diagnosed as type 1 diabetes have non-autoimmune monogenic diabetes. The distinction has important therapeutic implications but, given the low prevalence and high cost of testing, selecting patients to test is important. We tested the hypothesis that low genetic risk for type 1 diabetes can substantially contribute to this selection. Methods: As proof of principle, we examined by exome sequencing families with 2 or more children, recruited by the Type 1 Diabetes Genetics Consortium (T1DGC) and selected for negativity for 2 autoantibodies and absence of risk human leukocyte antigen haplotypes. Results: We examined 46 families that met the criteria. Of the 17 with an affected parent, 7 (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including 5 with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entireT1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones. Conclusions: Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that nonsyndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes.
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