Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration,Diabetes Care

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Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration
Diabetes Care ( IF 14.8 ) Pub Date : 2021-10-01 , DOI: 10.2337/dc21-0491
Jennifer N Todd _{1,

2,

3,

4} , Jeffrey W Kleinberger ₅ , Haichen Zhang ₅ , Shylaja Srinivasan ₆ , Sherida E Tollefsen ₇ , Lynne L Levitsky ₈ , Lorraine E Levitt Katz ₉ , Jeanie B Tryggestad ₁₀ , Fida Bacha ₁₁ , Giuseppina Imperatore ₁₂ , Jean M Lawrence ₁₃ , Catherine Pihoker ₁₄ , Jasmin Divers ₁₅ , Jason Flannick _{2,

3} , Dana Dabelea ₁₆ , Jose C Florez _{3,

4,

17,

18} , Toni I Pollin ₁₉

Affiliation

Division of Pediatric Endocrinology, Department of Pediatrics, University of Vermont, Burlington, VT.
Department of Pediatrics, Boston Children's Hospital, Boston, MA.
Program in Medical and Population Genetics, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
Division of Pediatric Endocrinology, University of California, San Francisco, San Francisco, CA.
Department of Pediatrics, Saint Louis University Health Sciences Center, St. Louis, MO.
Division of Pediatric Endocrinology, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Children's Hospital of Philadelphia, Perelman School of Medicine of University of Pennsylvania, Philadelphia, PA.
Section of Diabetes & Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX.
Centers for Disease Control and Prevention, Atlanta, GA.
Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA.
Department of Pediatrics, University of Washington, Seattle, WA.
New York University Langone Medical Center, New York, NY.
Lifecourse Epidemiology of Adiposity & Diabetes (LEAD) Center, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO.
Diabetes Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.
Department of Medicine, Harvard Medical School, Boston, MA.
Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD

OBJECTIVE

Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes.

RESEARCH DESIGN AND METHODS

We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines.

RESULTS

Of 3,333 participants, 93 (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs. 13.6 ± 2.3 years, P = 0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs. 4.7 ± 3.5 ng/mL, P < 0.0001). Youth with MODY were less likely to have hypertension (6.9% vs. 19.5%, P = 0.007) and had higher HDL cholesterol (43.8 vs. 39.7 mg/dL, P = 0.006).

CONCLUSIONS

By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n = 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.

中文翻译：

推测患有 2 型糖尿病的青少年中的单基因糖尿病：青少年糖尿病遗传学 (ProDiGY) 合作进展的结果

客观的

青少年发病的糖尿病 (MODY) 经常被误诊为 1 型或 2 型糖尿病。正确的诊断可能会导致临床治疗的改变并影响并发症和家族风险的预测。在这项研究中，我们旨在评估临床诊断为 2 型糖尿病的 20 岁以下多民族青年中 MODY 的患病率。

研究设计和方法

我们评估了临床诊断为 2 型糖尿病的青少年的全外显子序列数据。如果参与者携带 MODY 基因变体，根据当前指南分类为可能致病 (LP) 或致病 (P)，我们认为他们患有 MODY。

结果

在 3,333 名参与者中，93 名（2.8%）在HNF4A （16 名参与者）、 GCK （23 名）、 HNF1A （44 名）、 PDX1 （5 名）、 INS （4 名）和CEL （1 名）中携带 LP/P 变异。与没有 LP/P 变异的青少年相比，患有 MODY 的青少年诊断时年龄较小（12.9 ± 2.5 比 13.6 ± 2.3 岁， P = 0.002），空腹 C 肽水平较低（3.0 ± 1.7 比 4.7 ± 3.5）纳克/毫升， P < 0.0001）。患有 MODY 的青少年患高血压的可能性较小（6.9% vs. 19.5%， P = 0.007），并且 HDL 胆固醇较高（43.8 vs. 39.7 mg/dL， P = 0.006）。