Maturity-Onset Diabetes of the Young (MODY) is an autosomal dominant form of non-ketotic diabetes mellitus with typical onset before age 25. Accounting for 1-5% of all diabetes, MODY may affect 500,000 – 1 million people in the US. Mutations in five different genes are associated with different presentations of disease, named MODY1 through MODY5 as described below.

MODY may be mislabeled as Type 1 or Type 2 diabetes and genetic testing should be considered for patients with:

• Diabetes onset before age 25 in absence of autoantibodies
• Normal body weight
• Family history of diabetes
• Endogenous insulin production 3 years after diagnosis
• No evidence for insulin resistance
• No acanthosis nigricans

MODY1:	This is a less-common type of MODY that shares with MODY3 the features of vascular complication risk, progressive loss of glucose tolerance, and response to sulfonylurea drugs. The causative gene is HNF4A.
MODY2:	This is the second most common type of MODY, causing mild fasting hyperglycemia and little risk of vascular disease. It is usually managed by diet alone. The causative gene is GCK.
MODY3:	This is the most common type of MODY. It shares with MODY1 an increased risk of vascular complications, progressive deterioration in glucose tolerance with age, and response to sulfonylurea drugs. Eventually approximately one third of patients will require insulin. A slightly lower age of diagnosis, low renal threshold for glycosuria, and normal rather than reduced circulating lipoproteins and triglycerides in MODY3 may help differentiate it from MODY1. The causative gene is TCF1, also called HNF1A.
MODY4:	This is a very rare type of MODY with clinical severity intermediate between MODY2 and MODY1/MODY3. The causative gene is IPF1.
MODY5:	This type of diabetes is part of a multisystem disorder called Renal Cysts and Diabetes (RCAD) Syndrome. Most patients will have renal cysts or other developmental abnormalities of the kidneys that precede the onset of diabetes of variable severity (mean onset age 26 years). Other features may include malformations of the female genital tract, elevated liver enzymes, and hyperuricemia. The causative gene is TCF2, also called HNF1B.

• Differentiation of MODY from Type 1 or early Type 2 diabetes


• For optimal management by diet (MODY2), sulfonylurea drugs
  (MODY3, MODY1), or insulin


• Determine prognosis


• Identify family members at high risk for diabetes

The Ambry SEQUENCE: MODY is a testing pathway to sequentially analyze for mutations causing the three major MODY types in order of frequency: MODY3, then MODY2, then MODY1. Unnecessary testing is avoided by starting with the most common genetic cause and reflexing through analyses of less commonly responsible genes. Testing begins with full gene analysis of TCF1, which is mutated in approximately 58% of MODY patients. Patients who are negative for TCF1 mutations are then automatically tested for GCK mutations, positive in approximately 35% of patients. Further analysis for HNF4A mutations in TCF1- and GCK-negative patients yields a genetic diagnosis in nearly 5% of cases for overall molecular diagnostic confirmation in over 90% of MODY patients. Measures of proportion of MODY cases detectable by molecular testing do vary in the literature depending on the population studied and these detection rates are estimates.

In addition to the Ambry SEQUENCE, testing is available separately or in any combination for all five MODY genes GCK, HNF4A, IPF1, TCF1, and TCF2.

    General Test Information
Ambry Test: HNF4A-Related Diabetes (MODY1)
    (Abobe PDF document)

    General Test Information
Ambry Test: GCK-Related Diabetes (MODY2)
    (Abobe PDF document)

    General Test Information
Ambry Test: TCF1-Related Diabetes (MODY3)
    (Abobe PDF document)

    General Test Information
Ambry Test: IPF1-Related Diabetes (MODY4)
    (Abobe PDF document)

    General Test Information
Ambry Test: TCF2-Related Diabetes (MODY5 or RCAD)
    (Abobe PDF document)

The following CPT Codes for The Ambry Test reflect Ambry Genetics’ interpretation of CPT coding requirements based on AMA guidelines:

Ambry SEQUENCE: MODY
83891, 83894, 83898, 83904, 83909, 83912

Ambry Test: HNF4A-Related Diabetes (MODY1)
83891, 83894, 83898, 83904, 83909, 83912

Ambry Test: GCK-Related Diabetes (MODY2)
83891, 83894, 83898, 83904, 83909, 83912

Ambry Test: TCF1-Related Diabetes (MODY3)
83891, 83894, 83898, 83904, 83909, 83912

Ambry Test: IPF1-Related Diabetes (MODY4)
83891, 83894, 83898, 83904, 83909, 83912

Ambry Test: TCF2-Related Diabetes (MODY5 or RCAD)
83891, 83894, 83898, 83904, 83909, 83912

CPT codes are provided only as a guide to assist you in billing. CPT coding is the sole responsibility of the billing party.

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Disclaimer:

This test was developed and its performance characteristics were determined by Ambry Genetics Corporation. The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform nonwaived testing. The Ambry Tests described above analyze the following types of mutations: nucleotide substitutions, small deletions, small insertions, and small indels. They are not intended to analyze the following types of mutations: gross insertions, gross rearrangements, deep intronic variations, and other unknown abnormalities. The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated. A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group.
The following four Ambry Tests described above are designed and validated to be capable of detecting about 99% of mutations in the genes listed (considering less than 1% to be the other types of mutations): HNF4A, GCK, TCF1, IPF1. The Ambry Test: TCF2-Related Diabetes is designed and validated to be capable of detecting about 95% of TCF2 mutations (considering about 5% to be the other types of mutations). Given the apparent frequency of large deletions in TCF2 mutation carrying patients, the detection rate is about 63%. Diabetes, pancreatic agenesis, and/or RCAD are complex clinical disorders, which in some cases are due to alterations in the genes listed generally detected by the Ambry Test except as noted above. Mutations in other genes or the regions not tested by the Ambry Test, or disease processes not yet related to genetics, can also give rise to clinical conditions similar or identical to MODY or RCAD. Although molecular tests are highly accurate, rare diagnostic errors may occur. Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. This report does not represent medical advice. Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature. References are available upon request.