Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Permalink Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)
GENE/GENE PANEL:
HNF1A
Condition:
Maturity Onset Diabetes of the Young Type III
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of mature onset diabetes of the young (MODY) has been well characterized in European and North American populations but not in African and Asian populations. The minimum population prevalence of MODY in the United Kingdom (UK) is estimated at 108 cases per million. Studies of population-based childhood diabetes registries estimated the minimum prevalence of monogenic diabetes as 3.1/100,000 in Norwegian children, 4.2-4.6/100,000 in Polish children, 2.39/100,000 in German children, and 2.1/100,000 in American children. The frequency of the different genetic subtypes, including MODY3, is variable and greatly depends on the clinical recruitment (either pediatric or adult).
Clinical Features
(Signs / symptoms)
(Signs / symptoms)
MODY is a form of familial diabetes characterized by an early age of onset and by impaired insulin secretion with little or no defects in insulin action. Cases of MODY3 can be misdiagnosed as familial type 1 or type 2 diabetes because the clinical features are similar. Patients with MODY3 have decreased renal absorption of glucose (i.e., a low renal threshold for glucose) and glycosuria. Lacking are features typical of type 1 diabetes (islet autoantibodies, insulin requirements 5 years after diagnosis) or early-onset type 2 diabetes (high BMI, hypertension, dyslipidemia, acanthosis nigricans). In addition, patients are at risk for familial liver adenomatosis and hemorrhage.
Natural History
(Important subgroups & survival / recovery)
(Important subgroups & survival / recovery)
The MODY3 subtype (associated with mutations in the HNF1A gene) is the most common in undiagnosed adults. Glucose intolerance becomes evident during adolescence or early adulthood, with an age of onset generally before 40 years. In the early stages of disease, fasting blood glucose may be normal but patients tend to show a large increment in blood glucose after meals or during an oral glucose tolerance test. Over time, fasting hyperglycemia and osmotic symptoms become evident but typically without ketosis. The disease is progressive and patients have a similar risk of microvascular complications (e.g., retinopathy, neuropathy, or nephropathy) as patients with type 1 and type 2 diabetes. Similarly, patients are also at an increased risk of cardiovascular disease. Exposure to maternal diabetes in utero (if the mutation is maternally inherited) lowers the age of onset.
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Persons who are positive for an HNF1A mutation and who develop clinical symptoms can initially be treated with diet. With progressive deterioration in glycemic control, low-dose sulfonylureas are recommended as the first-line treatment, which differs from treatment recommendations for other forms of diabetes. In a series of 43 misclassified diabetic patients initially treated with insulin, 34 changed from insulin to a sulfonylurea after detection of an HNF1A mutation and 24 remained off insulin for 39 months with no deterioration in glycemic control. Successful transfer from insulin to sulfonylurea was correlated with a shorter duration of diabetes prior to changing treatment and emphasizes the need for early genetic diagnosis.
(Tier 3)
Patients with MODY3 are at risk of vascular complications and cardiovascular disease. Thus statin therapy is recommended by age 40, regardless of lipid status. In one study of 39 families (mutation carriers [n=153] vs. non-carriers [n=241], no correction for multiple family members, no information on statin treatment), the hazard ratio for cardiovascular death was 2.6 (95% CI, 1.5-4.4, p=0.001).
(Tier 3)
Surveillance
Annual screening for diabetes in asymptomatic mutation carriers is recommended from the age of 10.
(Tier 3)
Family Management
First-degree relatives will be at 50% risk of inheriting the mutation and asymptomatic individuals may be offered predictive genetic testing (after appropriate genetic counseling) in order to provide reassurance (for those shown not to carry the mutation) or regular blood glucose monitoring with early diagnosis and appropriate treatment (for mutation carriers and those at risk who refuse genetic testing).
(Tier 4)
First degree diabetic relatives of patients with HNF1A mutations should be offered genetic testing. This allows for the correct diagnosis in affected relatives who may be misclassified and not adequately treated. Genetic confirmation of MODY and assessment of endogenous insulin production in insulin-treated patients is essential before undertaking a change in treatment.
(Tier 4)
Circumstances to Avoid
Information on circumstances to avoid was not available.
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
Approximately 52% of confirmed UK MODY families have HNF1A mutations. Based on a U.S. MODY condition prevalence of 2.1/100,000, HNF1A mutation prevalence is estimated at 1.1 per 100,000.
(Tier 3)
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Expressivity
The clinical expression of MODY3 varies widely, partly due to environmental and genetic factors, including the characteristics of the HNF1A mutation itself.
(Tier 5)
4. What is the Nature of the Intervention?
Nature of Intervention
Surveillance involves routine blood tests. Treatment with an oral sulfonylurea is associated with possible side effects of weight gain and hypoglycemia.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Without a correct genetic diagnosis, persons at risk and their family members may be incorrectly diagnosed with type 1 or type 2 diabetes, leading to suboptimal treatment, delays in obtaining a correct diagnosis, potential progression of disease sequelae, and delays in diagnosing other family members.
(Tier 3)
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Intervention
Total
Score
Score
Suboptimal glycemic control / Sulfonylureas/ optimal diabetic control
2
3C
3C
3
11CC
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Date of Search:
08.26.2015
Reference List
1.
.
Clinical utility gene card for: maturity-onset diabetes of the young.
Eur J Hum Genet.
(2014)
22(9).
2.
Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD.
Maturity-onset diabetes of the young, type 3; mody3.
MIM: 600496:
2009 Feb 19.
World Wide Web URL: http://omim.org.
3.
.
The diagnosis and management of monogenic diabetes in children and adolescents.
Pediatr Diabetes.
(2014)
15 Suppl 20:47-64.