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Test Code LAB1884 MODY Sequencing

Clinical System Name

MODY Sequencing

Description

Main features of Maturity Onset Diabetes of the Young (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.

 

Our expanded MODY panel, includes sequencing of the following genes and an estimated detection rate of greater than 90% of individuals with MODY: ABCC8, APPL1, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, INS-IGF2, KCNJ11, KLF11, NEUROD1, PAX4, PDX1.  

 

Targeted gene and targeted variant testing are also available for the genes in our panel.  Targeted analysis for sequence variants previously identified through clinical testing of a family member or research testing of the individual.  Please provide copies of proband reports when requesting known mutation analysis for cases NOT performed by Seattle Children's Lab.

Sample Requirements

Note: For patients who have had a whole blood transfusion, wait 10 days post transfusion to draw for genetic testing. No wait time is necessary for blood or saliva collection if the patient received leuko-reduced red cells or plasma.

 

Specimen: Whole blood

Container(s): Lavender/EDTA

Preferred Vol: 3 mL

Minimum Vol: 1 mL

 

Specimen: Saliva collected using Oragene Dx OGD-575/675 collection kit.

Container: Oragene Dx OGD-575/675 collection kit

IMPORTANT NOTE: Manufacturer instructions must be followed. The Oragene Dx OGD575/675 kit is not for children under 6 months. Contact the lab directly for more information or to obtain a kit - 206-987-2563, ReferenceLabTeam@seattlechildrens.org.

 

Specimen: Extracted DNA (MUST specify source on requisition)

Preferred: 10µg

Minimum: 5µg

Note: Isolation of nucleic acids for clinical testing must be performed in a CLIA-certified
laboratory or a laboratory meeting equivalent requirements as determined by the CAP
and/or the CMS. DNA concentration minimum 50 µg/mL; 260/280 ratio 1.70-2.00.

Processing Instructions

Reject due to: Heparin

Spin: No

Aliquot: No

Temp: 2 - 8 C

Storage location: Molecular Genetics box in CPA refrigerator #2

Off-site collection: Refrigerate blood samples until ready to ship.  Transport all sample types at room temperature via overnight shipping.

Stability

Specimen Type Temperature Time
Whole blood, extracted DNA RT 3-5 d
Whole blood, extracted DNA 2 - 8 C 7 d

Saliva, extracted from ORAgene Dx OGD-575/675

 room temperature or refrigerated up to 2 weeks
Extracted DNA -20 C or -70 C  years

Note: Whole blood samples > 7days may be submitted to be assessed by our lab for acceptability for testing.

Availability

STAT Performed TAT
Contact lab Monday - Friday 4-6 weeks

 

Performing Laboratory

Seattle Children's Laboratory

Department

Department:  Molecular Genetics Laboratory

Phone: 206-987-3872

Lab Client Services: 206-987-2617

Lab Genetic Counselor: LabGC@seattlechildrens.org

CPT Codes

MODY panel: 81479

Call or email Lab Client Services, 206-987-2617, labclientservices@seattlechildrens.org, for targeted gene or targeted variant CPT codes.

Methodology

Method: Next Generation Sequencing technology using an Illumina NextSeq instrument. Target region includes coding exons and a minimum of 10 bp of flanking intron boundaries of the genes tested. Target enrichment performed using a custom Integrated DNA Technologies (IDT) Exome Hyb Panel v2.

 

Average coverage ~150x, depth of coverage for all target regions is at least 20x except exon 9 of the CEL gene (NM_001807.5).

 

Limitations: 

This testing is performed on an exome backbone with analysis restricted to the panel genes. This method can detect single nucleotide variants (SNVs), small deletions, small insertions, and copy number variants in the regions targeted. Some regions cannot be efficiently captured due to sequence homology or sequence properties. This method will not detect large insertions and deletions, complex indels, structural variants (e.g. inversions, translocations), short tandem repeats, or other complex variants. Variants located outside of targeted regions will not be detected.

 

Based on validation studies, the bioinformatics pipeline showed precision and detection >99% for SNVs in regions with coverage greater than 20x and high mapping quality. Sensitivity for CNVs involving multiple genes is >99% and sensitivity for intragenic CNVs is >90%. Mosaic sequence variants present at <25% allele frequency may not be reliably detected, and detection sensitivity is dependent on the nature of the variant. The sensitivity of detection of mosaic copy number variants has not been evaluated.

Reference Range

Interpretive report will be provided. Variants are not reported if they are considered benign.

Special Instructions

Links to: MODY GeneReviews; DiabetesGenes.org

Requisition

Molecular Genetics

Clinical Utility

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.

 

 

Genes Estimated percentage of individuals with MODY Phenotype
HNF1A (MODY 3) 30-65%
GCK (MODY 2) 30-50%
HNF4A (MODY 1) 5-10%
HNF1B 5%
ABCC8, APPL1, BLK, CEL, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1 <1% for each gene