Abstract
Objectives
There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY.
Methods
We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%.
Results
Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation.
Conclusions
Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.
Funding source: National Institutes of Health
Award Identifier / Grant number: P30DK26687
Funding source: National Institute of Diabetes and Digestive and Kidney Diseases
Award Identifier / Grant number: R01-DK52431T32 training grant 2T32DK065522
Funding source: Endocrine Fellows Foundation
Award Identifier / Grant number: Marilyn Fishman Grant for Diabetes Research
Acknowledgments
The authors gratefully thank the doctors at the Naomi Berrie Diabetes Center for referring eligible patients to their study, as well as referring providers across the country and globe who submitted patients. The authors thank the patients and their families for their contribution to research.
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Research funding: Research reported in this publication was supported by the NIDDK NRSA Institutional Research Training Grant (T32) 2T32DK065522 (PI Oberfield), Endocrine Fellows Foundation Grant, DK52431 (RLL), and P30DK26687 (WKC).
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Author contributions: Emily Breidbart and Wendy K. Chung designed the study. Emily Breidbart carried out the data collection, WES analysis, and wrote the initial draft of this paper. Liyong Deng, Charles LeDuc, and Jiancheng Guo performed and analyzed the Sanger sequencing. Patricia Lanzano coordinated data collection and kept the database. Xiao Fan helped with the WES analysis. Rudy L. Leibel gave input throughout the study and critically reviewed the data. Wendy K. Chung supervised each stage of the research and was the second reviewer of this manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Competing interests: The funding organization played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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Ethical approval: The study was reviewed and approved by the Institutional Review Board at Columbia University (IRB-AAAA4485). All participants provided written informed consent.
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Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2020-0501).
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