Maturity Onset Diabetes of the Young Type I & Type III

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: HNF1A (HGNC:11621) HNF4A (HGNC:5024)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 12/22/2022
• Curation Status: Released (2.0.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
HNF1A	maturity-onset diabetes of the young type 3 (0010894)	600496	Strong Actionability
HNF4A	maturity-onset diabetes of the young type 1 (0007452)	125850	Moderate Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion of strong for HNF1A (MODY3) and moderate for HNF4A (MODY1) computed according to the rubric. Data on effectiveness are lacking for MODY1.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Diabetes-related morbidity and mortality / Evaluation by specialist to guide management, including with sulfonylureas	1	3N	3D	3	10ND
Diabetes-related morbidity and mortality / Evaluation by specialist to guide management, including with sulfonylureas	1	2N	2D	3	8ND

Severity of Outcome

Prevalence of the Genetic Condition

Obtaining accurate prevalence data for maturity-onset diabetes of the young (MODY) is challenging because of overlapping clinical features with more common types of diabetes (type 1 and type 2) and lack of widespread genetic testing. Studies of population-based childhood diabetes registries estimated the minimum prevalence of monogenic diabetes in children as 2.1 to 4.6/100,000. Monogenic diabetes accounts for 2.5-6% of children with diabetes. MODY is the most common type of monogenic diabetes and MODY3 and MODY1 account for 30-65% and 5-10% of all patients with MODY, respectively. The prevalence of MODY in members of historically underserved racial and ethnic groups may be underestimated as many individuals with MODY remain undiagnosed.

Clinical Features (Signs / symptoms)

MODY3 and MODY1 are monogenic forms of non-autoimmune diabetes mellitus. In MODY3, transient neonatal hyperinsulinemic hypoglycemia can occur but is very uncommon. In MODY1, babies can have transient hyperinsulinemic hypoglycemia and macrosomia. Chronic complications of diabetes such as microvascular disease (e.g., retinopathy, neuropathy, or nephropathy) can occur at increased frequencies in both MODY3 and MODY1, and their development is related to the degree of glycemic management. MODY3 is also associated with an increased frequency of cardiovascular disease and mortality. Features typical of type 1 diabetes (islet autoantibodies, insulin requirements 5 years after diagnosis) are lacking. Features of insulin resistance such as high BMI, hypertension and dyslipidemia are less prevalent in patients with MODY3 and MODY1 compared with patients with early-onset type 2 diabetes. In addition, patients with a pathogenic variant in HNF1A (MODY3) may be at increased risk for familial liver adenomatosis. Patients with the p.Arg76Trp pathogenic variant in HNF4A (MODY1) present with an atypical form of Fanconi syndrome including hypercalciuria and nephrocalcinosis in addition to diabetes.

Natural History (Important subgroups & survival / recovery)

Glucose intolerance usually becomes evident during adolescence or early adulthood, with an age of onset generally before 35 years. Prior to developing overt diabetes, individuals with MODY3 and MODY1 have marked progressive beta cell dysfunction, increased insulin sensitivity, and glycosuria. 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 (polyuria, polydipsia) become evident but typically without ketosis. Individuals with MODY3 have been reported to be more likely to die from cardiovascular disease and at younger ages than their unaffected family members. Exposure to maternal diabetes in utero (if the pathogenic variant is maternally inherited) lowers the age at onset of diabetes by about 12 years. Individuals with pathogenic missense variants in the first six exons of HNF1A are diagnosed on average 8 to 12 years earlier than those individuals with missense variants located in exons 8-10 or in the transactivation domain. Patients with HNF1A truncating variants are diagnosed at a median age of 20 years independently of the location of the variant within HNF1A. A similar correlation was observed with HNF4A pathogenic variants.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

< 1-2 in 100000

In a US health system-based cohort of 132,194 clinically unselected individuals, there were 14 individuals with pathogenic variants in HNF1A (prevalence of 0.011%; MODY3) and 17 individuals with pathogenic variants in HNF4A (prevalence of 0.013%: MODY1). In a UK Biobank cohort of 198,748 individuals, there were 22 individuals with pathogenic variants in HNF1A (prevalence of 0.011%) and 29 individuals with pathogenic variants in HNF4A (prevalence of 0.015%).

Tier 5

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

The diabetes in MODY3 and MODY1 is progressive and the penetrance increases with age. For MODY3 penetrance is approximately 63% by age 25 years, 79% before age 35, and 96% before 55 years.

Tier 3

>= 40 %

Penetrance of MODY3 and MODY1 is lower in clinically unselected cohorts. The penetrance of diabetes by age 40 for pathogenic HNF1A variants (MODY3) was 98% in probands referred for genetic testing (n=661), 86% in family members of the probands (n=954), 49% in a US health system-based cohort of unselected individuals (n=14), and 32% in a UK Biobank (n=17). The penetrance of diabetes by age 40 years for pathogenic HNF4A variants (MODY1) was 98% in probands referred for genetic testing (n=142), 76% in family members of probands (n=253), 5% in a US health system-based cohort of unselected individuals (n=22), and 17% in a UK Biobank (n=29).

Tier 5

>= 40 %

Various studies have reported rates of diabetes complications in individuals with MODY3.

• Diabetic retinopathy in 47.7%

• Proliferative retinopathy in 13 to 21%

• Diabetic nephropathy in 25%

• Cardiovascular disease in 9.1 to 16%

Tier 5

5-39 %

Liver adenomatosis was found in 6.5% (n=9/137) of patients with MODY3 in one cohort.

Tier 4

>= 40 %

About 50% of babies with MODY1 are macrosomic at birth and 15% have neonatal hyperinsulinemic hypoglycemia.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was found.

Expressivity

The clinical expression of MODY3 varies widely, partly due to environmental and genetic factors, including the characteristics of the HNF1A pathogenic variant itself.

Tier 5

Intervention Effectiveness

Patient Management

Referral to a specialist in monogenic diabetes or an interested clinical genetics unit is suggested to guide specific management considerations.

Tier 2

Persons who are positive for a pathogenic variant in HNF1A or HNF4A 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 the US, glyburide is the most commonly used sulfonylurea. The initial dose of sulfonylureas should be low (one-quarter of the normal starting dose in adults) to avoid hypoglycemia. If there are no problems with hypoglycemia, patients can be maintained on low-dose sulfonylureas for decades. In patients with hypoglycemia, treatment with meglitinides can be considered. Over time the glycemic control of sulfonylureas may deteriorate, especially in those who are obese. The best augmentative therapy is unclear; GLP-1 agonists and insulin therapy are appropriate options. In a MODY3 screening study, a total of 60 patients (ranging in age from 21-49 years) from 20 families with a confirmed pathogenic variant in HNF1A were identified. Of the 60 patients, 32 were not on sulphonylurea treatment at the time of their genetic diagnosis and a change in their treatment regimen to sulphonylurea only was made. A further 12/60 were already treated with sulphonylurea at the time of their genetic diagnosis. After a median follow-up period of 84 months, 26 of these 44 patients (59.1%) were maintained on sulphonylurea treatment alone. There were no episodes of severe hypoglycemia. Those who were successfully treated with sulphonylurea monotherapy had a significant improvement in HbA1C [49 mmol/mol, 6.6% vs. 41 mmol/mol, 5.9%; P=0.003]. Those that required an additional therapeutic agent had a longer duration of diabetes and had a higher HbA1C at initial presentation to the MODY clinic. The rates of both micro- and macrovascular complications were lower in this cohort than those of other reported cohorts. Retinopathy was detected in 13.6% of the 60 patients and proliferative retinopathy in 3.3%. Nephropathy was detected in 5% and coronary heart disease in 6.7%.

Tier 3

It is reasonable to assume that individuals with MODY1 (like those with MODY3) may respond to meglitinides and GLP-1 agonists; however, no formal data support this assumption.

Tier 4

Neonates with MODY1 are at risk of neonatal hyperinsulinemic hypoglycemia and blood glucose should be checked from birth.

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 (carriers of pathogenic variants [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). Those with a pathogenic variant in HNF1A died younger than the control subjects from all causes. Of those who died, 66% of individuals with a pathogenic variant died from a cardiovascular-related illness compared with 43% of control subjects (p=0.02).

Tier 3

Surveillance

Annual screening for diabetes in asymptomatic individuals with a pathogenic variant is recommended from the age of 10.

Tier 4

Circumstances to Avoid

Information on circumstances to avoid was not available.

Nature of Intervention

Nature of Intervention

Surveillance involves routine blood tests. Treatment with an oral sulfonylurea can cause hypoglycemia, which may limit their use in some patients. Hypoglycemia is generally mild, though can be severe especially in combination therapy with insulin. There are concerns regarding placental transfer of sulfonylureas. A meta-analysis showed increased risk of macrosomia and neonatal hypoglycemia in pregnancies treated with the sulfonylurea glyburide compared to insulin.

Context: Adult Pediatric

Chance to Escape Clinical Detection

MODY3 and MODY1 cannot be diagnosed using non-genetic tests alone. Without a correct genetic diagnosis, persons with MODY3 and MODY1 may be incorrectly diagnosed with type 1 or type 2 diabetes, leading to suboptimal treatment, delays in obtaining a correct diagnosis, and potential progression of disease sequelae. Obesity has become so common in children that children and adolescents with monogenic diabetes may also be obese and can be very difficult to distinguish from type 1 diabetes.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			HNF1A			600496	0010894	0018911, 0015967
HNF4A			125850	0007452	0018911, 0015967

References List

Bacon S, Kyithar MP, Rizvi SR, Donnelly E, McCarthy A, Burke M, Colclough K, Ellard S, Byrne MM. (2016) Successful maintenance on sulphonylurea therapy and low diabetes complication rates in a HNF1A-MODY cohort. Diabetic medicine : a journal of the British Diabetic Association. 33(1464-5491):976-84.

Bellanne-Chantelot C, Levy DJ, Carette C, Saint-Martin C, Riveline JP, Larger E, Valero R, Gautier JF, Reznik Y, Sola A, Hartemann A, Laboureau-Soares S, Laloi-Michelin M, Lecomte P, Chaillous L, Dubois-Laforgue D, Timsit J. (2011) Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of the HNF1A gene. The Journal of clinical endocrinology and metabolism. 96(8):E1346-51.

Colclough K, Saint-Martin C, Timsit J, Ellard S, Bellanne-Chantelot C. (2014) Clinical utility gene card for: Maturity-onset diabetes of the young. European journal of human genetics : EJHG. 22(9).

Greeley SAW, Polak M, Njølstad PR, Barbetti F, Williams R, Castano L, Raile K, Chi DV, Habeb A, Hattersley AT, Codner E. (2022) ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatric diabetes. 23(1399-5448):1188-1211.

MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3; MODY3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 600496, (2009) World Wide Web URL: http://omim.org/

Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM, Geisinger-Regeneron DiscovEHR Collaboration, Frayling TF, Hattersley AT, Carey DJ, Weedon MN, Patel KA. (2022) Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. American journal of human genetics. 109(1537-6605):2018-2028.

MODY. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=552

Naylor R, Knight Johnson A, del Gaudio D. (1993) Maturity-Onset Diabetes of the Young Overview. GeneReviews^®.

Urbanova J, Brunerova L, Broz J. (2019) Hypoglycemia and antihyperglycemic treatment in adult MODY patients - A systematic review of literature. Diabetes research and clinical practice. 158(1872-8227):107914.