Genetic Testing in Diabetes Mellitus

Here, we review data on monogenic diabetes mellitus in Norway based on the Norwegian MODY Registry at Haukeland University Hospital, Bergen. This registry comprises established or suspected cases of maturity-onset diabetes of the young (MODY) referred to our laboratory for genetic testing. We also present data on neonatal diabetes, another group of monogenic diabetes. To date, we have genetically diagnosed nearly 500 MODY cases in Norway. Mutations in the HNF1A gene (MODY3) were detected in about 50% of families with clinical MODY. GCK-MODY (MODY2) was the second most prevalent type, but may be underreported. We have also found mutations in the monogenic genes ABCC8, CEL, HNF1B, HNF4A, INS, KCNJ11 and NEUROD1. Based on genetic screening in the Norwegian MODY Registry and HUNT2, we estimate the number of MODY cases in Norway to be at least 2500-5000. Founder effects may determine the geographical distribution of MODY mutations in Norway. The molecular genetic testing of MODY and neonatal diabetes is mandatory for correct diagnosis and prognosis as well as choice of therapy

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A case with relapsed transient neonatal diabetes mellitus treated with sulfonylurea, ending chronic insulin requirement

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-18-0005 ◽

2018 ◽

Vol 2018 ◽

Author(s):

Akihiko Ando ◽

Shoichiro Nagasaka ◽

Shun Ishibashi

Keyword(s):

Diabetes Mellitus ◽

Genetic Testing ◽

Glycaemic Control ◽

Genetic Defect ◽

Neonatal Diabetes ◽

Insulin Requirement ◽

Neonatal Diabetes Mellitus ◽

List Type ◽

Sulfonylurea Receptor ◽

Early Screening

Summary We report a case of a woman with diabetes mellitus caused by a genetic defect in ABCC8-coding sulfonylurea receptor 1 (SUR1), a subunit of the ATP-sensitive potassium (KATP) channel protein. She was diagnosed with diabetes at 7 days after birth. After intravenous insulin drip for 1 month, her hyperglycaemia remitted. At the age of 13 years, her diabetes relapsed, and after that she had been treated by intensive insulin therapy for 25 years with relatively poor glycaemic control. She was switched to oral sulfonylurea therapy and attained euglycaemia. In addition, her insulin secretory capacity was ameliorated gradually. Learning points: Genetic testing should be considered in any individuals or family with diabetes that occurred within the first year or so of life. Sulfonylurea can achieve good glycaemic control in patients with KATP channel mutations by restoring endogenous insulin secretion, even if they were treated with insulin for decades. Early screening and genetic testing are important to improve the prognosis of patients with neonatal diabetes mellitus arising from ABCC8 or KCNJ11 mutation.

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Into the Future: Genetic Testing for Type 2 Diabetes Mellitus

Southern Medical Journal ◽

10.1097/00007611-200211000-00028 ◽

2002 ◽

Vol 95 (11) ◽

pp. 1357-1358

Author(s):

Matthew B. Totten ◽

Debra L. Simmons

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Genetic Testing ◽

The Future

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Molecular and clinical characteristics of monogenic diabetes mellitus in southern Chinese children with onset before 3 years of age

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001345 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001345

Author(s):

Yunting Lin ◽

Huiying Sheng ◽

Tzer Hwu Ting ◽

Aijing Xu ◽

Xi Yin ◽

...

Keyword(s):

Diabetes Mellitus ◽

Genetic Testing ◽

Age Of Onset ◽

Neonatal Diabetes ◽

Monogenic Diabetes ◽

Chinese Patients ◽

Combination Strategy ◽

Southern Chinese ◽

Whole Exome ◽

Design And Methods

IntroductionA specific molecular diagnosis of monogenic diabetes mellitus (MDM) will help to predict the clinical course and guide management. This study aims to identify the causative genes implicated in Chinese patients with MDM with onset before 3 years of age.Research design and methods71 children with diabetes mellitus (43 diagnosed before 6 months of age, and 28 diagnosed between 6 months and 3 years of age who were negative for diabetes-associated autoantibodies) underwent genetic testing with a combination strategy of Sanger sequencing, chromosome microarray analysis and whole exome sequencing. They were categorized into four groups according to the age of onset of diabetes (at or less than 6 months, 6 to 12 months, 1 to 2 years, 2 to 3 years) to investigate the correlation between genotype and phenotype.ResultsGenetic abnormalities were identified in 39 of 71 patients (54.93%), namely KCNJ11 (22), ABCC8 (3), GCK (3), INS (3), BSCL2 (1) and chromosome abnormalities (7). The majority (81.40%, 35/43) of neonatal diabetes diagnosed less than 6 months of age and 33.33% (3/9) of infantile cases diagnosed between 6 and 12 months of age had a genetic cause identified. Only 11.11% (1/9) of cases diagnosed between 2 and 3 years of age were found to have a genetic cause, and none of the 10 patients diagnosed between 1 and 2 years had a positive result in the genetic analysis. Vast majority or 90.48% (19/21) of patients with KCNJ11 (19) or ABCC8 (2) variants had successful switch trial from insulin to oral sulfonylurea.ConclusionsThis study suggests that genetic testing should be given priority in diabetes cases diagnosed before 6 months of age, as well as those diagnosed between 6 and 12 months of age who were negative for diabetes-associated autoantibodies. This study also indicates significant impact on therapy with genetic cause confirmation.

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Approach to the Patient with MODY-Monogenic Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa710 ◽

2020 ◽

Vol 106 (1) ◽

pp. 237-250

Author(s):

David T Broome ◽

Kevin M Pantalone ◽

Sangeeta R Kashyap ◽

Louis H Philipson

Keyword(s):

Diabetes Mellitus ◽

Genetic Testing ◽

Family History ◽

Autoimmune Diabetes ◽

Clinical Manifestations ◽

Cost Effective ◽

Monogenic Diabetes ◽

Educational Activity ◽

Inherited Disorders ◽

Cost Effective Treatment

Abstract Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants). Learning Objectives Upon completion of this educational activity, participants should be able to: Target Audience This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.

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