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GeneDx
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: [email protected]
www.genedx.com
Test Information Sheet
Maturity-Onset Diabetes of the Young (MODY)
Mendelian Inheritance in Man Numbers:
MODY1 (125850) - HNF4A (600281); MODY2 (125851) – GCK (138079); MODY3 (600496) – HNF1A (142410);
MODY4 (606392) – PDX1 (aka IPF1; 600733); MODY5 (137920) – HNF1B (189907)
Clinical Features:
Maturity-onset diabetes of the young (MODY) is a monogenic form of insulin-independent diabetes that follows an
autosomal dominant pattern of inheritance and typically presents before the age of 25 years. MODY accounts for
approximately 1-2% of diabetes mellitus and can be difficult to differentiate from the more common forms of diabetes.
Differentiating factors include lack of autoantibodies usually observed with type 1 diabetes and lack of obesity often
observed with type 2 diabetes. However, establishing an accurate diagnosis and identifying its genetic etiology allow
for appropriate individualized management of symptoms and provide predictive and prognostic information for family
members. 1,2
Mutations in the HNF1A gene cause MODY3, which accounts for approximately 20-50% of MODY cases. The
phenotype associated with MODY3 is highly variable, with patients’ blood glucose levels ranging from normal to high.
Typically, individuals with MODY3 manifest in adolescence or early adult life with beta cell failure and progressive
hyperglycemia, putting patients at risk for microvascular and macrovascular complications. Hyperglycemic control can
be maintained for many years with sulfonylurea, although individuals with MODY3 often will ultimately progress to
insulin treatment. Mutations in the HNF4A gene cause MODY1, which accounts for approximately 5% of MODY
cases and has a similar presentation to MODY3. Heterozygous mutations in the PDX1 gene cause MODY4, which also
has a similar presentation but is a very rare cause of MODY. 1,2
MODY2 is caused by inactivating mutations in the GCK gene, accounting for another 20-50% of MODY cases.
Typically, patients with MODY2 have mild to moderate fasting hyperglycemia and are often asymptomatic. The
majority of individuals with MODY2 are managed with diet alone and rarely need pharmacological intervention. 1,2
Approximately 5% of MODY cases are due to mutations in the HNF1B gene, which causes MODY5. MODY5 is
characterized by renal disease and insulin resistance. Individuals with MODY5 have reduced pancreatic size, and
females may have urogenital abnormalities. Sulfonylurea treatment is ineffective for controlling hyperglycemia, and
insulin treatment is usually necessary. 1,2
Inheritance Pattern:
Autosomal Dominant.
Homozygous mutations in the GCK and PDX1 genes cause the rare autosomal recessive phenotype of permanent
neonatal diabetes. 3
Reasons for Referral:
1. Molecular confirmation of a clinical diagnosis
2. To assist with decisions about treatment and management of individuals with MODY
3. Testing of at-risk relatives for specific known mutation(s) previously identified in an affected family member
4. Prenatal diagnosis for known familial mutation(s) in at-risk pregnancies
Genes/Proteins:
The HNF4A, HNF1A, PDX1, and HNF1B genes (associated with MODY types 1, 3, 4 and 5, respectively) encode
transcription factors that regulate pancreatic β cell development and function. The GCK (associated with MODY2)
gene encodes glucokinase, an enzyme that enables β cells to accurately sense and respond to blood glucose
concentrations. Heterozygous inactivating mutations in the GCK gene causes beta cell insensitivity to blood glucose
concentrations, leading to a defect in insulin secretion.1,2
Information Sheet: MODY Panel
GeneDx 12/2015
Test Method:
Using genomic DNA from the submitted specimen, the coding regions and splice junctions of the five MODY genes
will be enriched using a proprietary targeted capture system developed by GeneDx. These targeted regions will be
sequenced simultaneously by massively parallel (NextGen) sequencing on an Illumina platform with paired-end reads.
Bi-directional sequence will be assembled, aligned to reference gene sequences based on human genome build
GRCh37/UCSC hg19, and analyzed for sequence variants. Capillary sequencing is used to confirm all potentially
pathogenic variants and to obtain sequence for regions where fewer than 15 reads were achieved by NextGen
sequencing. Concurrent deletion/duplication testing will be performed for the HNF1B gene using exon-level oligo array
CGH (ExonArrayDx). Data analysis will be performed using gene-specific filtering. Confirmation of copy number
changes will be performed by MLPA, qPCR, or repeat array CGH analysis.
Test Sensitivity:
MODY accounts for 1-2% of individuals with diabetes mellitus. Among individuals with MODY, approximately 2050% have a mutation in GCK gene (MODY2) and 20-50% have a mutation in the HNF1A gene (MODY3). Mutations
in the HNF4A (MODY1) gene and HNF1B (MODY5) gene each account for approximately 5% of MODY. Mutations
in the PDX1 gene (MODY4) are rare, and account for less than 1% of MODY.1,2
Mutation Spectrum:
Missense, nonsense, splicing, and insertion/deletion mutations have been reported in all five genes. Regulatory
mutations have been ported in HNF4A and HNF1A. Additionally, multiple individuals with MODY have been reported
to have gross deletions in the HNF1B gene (MODY5) as part of the 17q12 contiguous gene deletion syndrome.5,6
Specimen Requirements and Shipping/Handling:
 Blood: A single tube with 2-5 mL whole blood in EDTA. Ship overnight at ambient temperature, using a cool pack
in hot weather. Specimens may be refrigerated for 7 days prior to shipping.
 Buccal Brushes: NOT ACCEPTED
 Other specimens: Contact us for specific inquiries and specimen requests.
 Prenatal Diagnosis: Available only if a familial mutation has been identified. Contact us for more information
Required Forms:
 Sample Submission (Requisition) Form – complete all pages
 Payment Options Form or Institutional Billing Instructions
For test codes, prices, CPT codes, and turn-around-times, please refer to the “DISORDER” page on our website:
www.genedx.com
References
1. Gardner et al. (2012) Diabetes, Metabolic Syndrome And Obesity : Targets And Therapy 5 :101-8 (PMID:
22654519)
2. Steck et al. (2011) Current Opinion In Endocrinology, Diabetes, And Obesity 18 (4):252-8 (PMID: 21844708)
3. De León & Stanley (2008) [Updated 2011 Jul 5]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1447/
4. Raile et al. (2009) The Journal Of Clinical Endocrinology And Metabolism 94 (7):2658-64 (PMID: 19417042)
5. Mefford et al. (2007) American Journal Of Human Genetics 81 (5):1057-69 (PMID: 17924346)
Information Sheet: MODY Panel
GeneDx 12/2015