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Maturity-Onset Diabetes of the Young (MODY) Sequencing Panel

Maturity-Onset Diabetes of the Young (MODY) is an autosomal dominant form of diabetes typically occurring before age 25 and caused by a primary insulin secretion defect. MODY is not a single entity but represents nine classifications with genetic, metabolic, and clinical heterogeneity. MODY is estimated to affect approximately 1-2% of people with diabetes, although this may be an underestimate since the genetic etiology of this type of diabetes often goes undiagnosed.

Main features of MODY patients include the following: 1) Hyperglycemia usually diagnosed before age 25 years in at least 1 family member. 2) Autosomal dominant inheritance through at least 3 generations, and a phenotype shared by diabetic family members. 3) Absence of insulin therapy or significant C-peptide levels even in a patient on insulin treatment for several years after diagnosis.

The MODY panel tests for genetic mutations that cause MODY types 1, 2, and 3.

MODY 3 (HNF1A): This is the most common form of MODY, causing 60% of cases. It shares with MODY 1 the progressive hyperglycemia, risk for microvascular complications, and increasing need for treatment with sulfonylureas as the disease progresses. Approximately 1/3 of patients will ultimately require insulin to maintain euglycemia. Compared to MODY 1, patients with MODY 3 tend to have a lower renal threshold for glycosuria and a normal rather than reduced circulating lipoproteins and triglycerides, often with an elevated HDL. Despite the high HDL, the risk for coronary artery disease is increased in these patients.

MODY 2 (GCK): Approximately 25% of MODY is caused by mutations in the glucokinase (GCK) gene. It is associated with a mild form of nonprogressive hyperglycemia that is usually managed with diet alone. Individuals with GCK MODY rarely have overt symptoms of diabetes, and diabetes-associated complications are rare. These individuals are often diagnosed with diabetes or glucose intolerance on routine screening, particularly during pregnancy. Approximately 2-4% of gestational diabetes may be due to GCK mutations.

MODY 1 (HNF4A): Accounting for ~3% of MODY cases, MODY 1 is caused by mutations in the β-cell transcription factor gene, HNF4A. It has a similar presentation to MODY 3, including progressive hyperglycemia and microvascular complications. 30-40% of patients require sulfonylurea drugs or insulin over time.

Test Name: MODY Panel
Test Code:
MODY
Test Description:
Polymerase Chain Reaction (PCR) followed by sequence analysis of the entire coding region of each gene
Synonyms:
HNF1A, HNF4A, GCK, hyperglycemia
Indication:
GCK testing is indicated for individuals with the following clinical features:
1. Mild fasting hyperglycemia (100-145 mg/dl) that is stable over months to years
2. OGTT 2 hour glucose increment is usually <80 mg/dl
3. May have history of gestational diabetes that does not resolve post-partum
4. May have a family history of mild type 2 or gestational diabetes

HNF1A with reflex to HNF4A is indicated for individuals with the following clinical features:
1. Young onset diabetes (usually <25 years)
2. Prolonged non-insulin-requiring honeymoon period (>3 years) with evidence of residual beta-cell function:
a) Rare diabetic ketoacidosis
b) Good glycemic control on a small dose of insulin
c) Detectable C-peptide measured when on insulin

3. Large increment in blood glucose on OGTT (>80mg/dl), +/- normal fasting glucose
4. Strong, multigenerational family history of diabetes (may be diagnosed as either type 1 or 2 in different members)
5. Glycosuria at low levels of blood glucose
Related Tests:
Clinical Links: DiabetesGenes.Org (Peninsula Medical School, Exeter, UK)
Availability:
Mon - Fri
Turnaround Time:
2-4 weeks
Methodology:
PCR followed by sequencing
Reference Range:
Interpretive report will be provided
Requisition:
Consent Form:
Sample Requirements: Type
Whole blood: 3-5 mL in EDTA (purple top) or ACD (yellow top).
DNA: 5 micrograms extracted DNA.

Processing
Do not spin. Keep at room temperature. Refrigerate samples which are not shipped immediately.

Shipping
Room temperature via overnight shipping.
Samples Received:
Monday - Friday 8am - 5pm PST
Special Considerations:
Cost:
Please e-mail Lab Client Services (labclientservices@seattlechildrens.org) or call at 206-987-2617 with any billing questions
CPT Code:
Please e-mail Lab Client Services (labclientservices@seattlechildrens.org) or call at 206-987-2617 with any billing questions