MODY Panel

Last modified: Jun 12, 2018

Summary

  • Is a 13 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of maturity onset diabetes of the young (MODY).

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

3-4 weeks

Number of genes

13

Test code

EN0601

Panel size

Small

CPT codes

SEQ 81405
SEQ 81406
SEQ 81407
DEL/DUP 81479

Summary

The Blueprint Genetics MODY Panel (test code EN0601):

  • Is a 13 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) when ordering the MODY Panel

ICD-10 Disease
E11.9 Maturity-onset diabetes of the young

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

Maturity-onset diabetes of the young (MODY) is an autosomal dominant inherited form of diabetes and accounts for 1–2% of individuals with diabetes. MODY is a rare clinically and genetically heterogeneous form of diabetes characterized by young age of onset (generally 10-45 years of age), with development of non-insulin dependent diabetes prior to 25 years of age. Additionally, blood vessel abnormalities of the retinas (retinopathy) and kidneys, and congenital abnormalities due to diabetes complications have also been noted. Individuals with MODY typically have no reported history of obesity or metabolic syndrome accompanying hyperglycemia. Many people with MODY are misdiagnosed with type 1 or type 2 diabetes. MODY is the most common form of monogenic diabetes with an estimated prevalence at 1:10,000 in adults and 1:23,000 in children. Approximately 80% of cases are misdiagnosed as type 1 or type 2 diabetes, complicating prevalence and incidence estimations. Genetic testing is generally pursued only in those with classic features of MODY. However, only 50% of subjects with genetically diagnosed MODY meet classic criteria. Establishing a diagnosis of MODY significantly impacts clinical management. Heterozygous mutations in HNF1A, HNF4A, and GCK account for >90% of all MODY with a known genetic cause. Patients with HNF1A and HNF4A mutations have slowly progressing beta-cell dysfunction, and treatment with low-dose sulfonylurea results in stable or improved glycemic control and improved quality of life related to diabetes care compared with insulin or metformin therapy. GCK-MODY has a unique phenotype of mild, nonprogressive hyperglycemia, with HbA1c typically <7% (53 mmol/mol). It is not associated with increased risk of microvascular and macrovascular complications seen in other forms of diabetes. Generally, treatment does not change HbA1c. Molecular diagnosis of GCK-MODY allows pharmacologic therapy to be discontinued and decreases the frequency of medical surveillance. (PMID: 24026547).

Genes in the MODY Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCC8 Hyperinsulinemic hypoglycemia, Diabetes, permanent neonatal, Hypoglycemia, leucine-induced, Diabetes mellitus, transient neonatal AD/AR 128 621
BLK Maturity onset diabetes of the young AD 5 7
GCK Hyperinsulinemic hypoglycemia, familial, Diabetes mellitus, permanent neonatal, Maturity-onset diabetes of the young, type 2 AD/AR 179 825
HNF1A Maturity onset diabetes of the young, Renal cell carcinoma, nonpapillary clear cell, Liver adenomatosis AD 72 524
HNF1B Renal cell carcinoma, nonpapillary chromophobe, Renal cysts and diabetes syndrome AD 34 227
HNF4A Congenital hyperinsulinism, diazoxide-responsive, Maturity onset diabetes of the young, Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young AD 30 147
INS Diabetes mellitus, permanent neonatal, Hyperproinsulinemia, familial, with or without diabetes, Maturity onset diabetes of the young AD 33 76
KCNJ11 Hyperinsulinemic hypoglycemia, Diabetes, permanent neonatal, Diabetes mellitus, transient neonatal, Maturity-onset diabetes of the young 13, Paternally-inherited mutations can cause Focal adenomatous hyperplasia AD/AR 56 173
KLF11 Maturity onset diabetes of the young AD 1 3
NEUROD1 Maturity onset diabetes of the young AD 3 17
PAX4 Diabetes mellitus AD 3 10
PDX1 Pancreatic agenesis, Neonatal diabetes mellitus, Maturity-onset diabetes of the young, type 4, Lactic acidemia due to PDX1 deficiency AD/AR 10 26
RFX6 Pancreatic hypoplasia, intestinal atresia, and gallbladder aplasia or hypoplasia, with or without tracheoesophageal fistula, Martinez-Frias syndrome, Mitchell-Riley syndrome AR 10 28

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ABCC8 Chr11:17498513 c.-190C>G NM_000352.3
ABCC8 Chr11:17465872 c.1333-1013A>G NM_000352.3
BLK Chr8:11422122 c.*505G>T NM_001715.2
GCK Chr7:44229109 c.-557G>C NM_000162.3
HNF1A Chr12:121416453 c.-119G>A NM_000545.5 rs371945966
HNF1A Chr12:121416448 c.-124G>C NM_000545.5 rs563304627
HNF1A Chr12:121416385 c.-187C>A/T NM_000545.5
HNF1A Chr12:121416354 c.-218T>C NM_000545.5
HNF1A Chr12:121416314 c.-258A>G NM_000545.5 rs756136537
HNF1A Chr12:121416289 c.-283A>C NM_000545.5
HNF1A Chr12:121416285 c.-287G>A NM_000545.5
HNF1A Chr12:121416281 c.-291T>C NM_000545.5 rs534474388
HNF1A Chr12:121416110 c.-462G>A NM_000545.5
HNF1A Chr12:121416034 c.-538G>C NM_000545.5
HNF1A Chr12:121416510 c.-62C>G NM_000545.5 rs753567412
HNF1A Chr12:121416475 c.-97T>G NM_000545.5
HNF4A Chr20:42984309 c.-136A>G NM_175914.4
HNF4A Chr20:42984299 c.-146T>C NM_175914.4
HNF4A Chr20:42984276 c.-169C>T NM_175914.4
HNF4A Chr20:42984271 c.-174T>C NM_175914.4
HNF4A Chr20:42984264 c.-181G>A NM_175914.4
HNF4A Chr20:42984253 c.-192C>G NM_175914.4
HNF4A Chr20:43036000 c.291-21A>G NM_000457.4
INS Chr11:2181023 c.*59A>G NM_000207.2 rs397515519
INS Chr11:2181774 c.187+241G>A NM_000207.2
INS Chr11:2181242 c.188-15G>A NM_000207.2 rs574629011
INS Chr11:2181258 c.188-31G>A NM_000207.2 rs797045623
KCNJ11 Chr11:17409772 c.-134G>T NM_000525.3 rs387906398
KCNJ11 Chr11:17409692 c.-54C>T NM_000525.3
NEUROD1 Chr2:182545307 c.-162G>A NM_002500.4 rs537184640
RFX6 Chr6:117198947 c.224-12A>G NM_173560.3

Added and removed genes from the panel

Genes added Genes removed
RFX6

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics MODY panel covers classical genes associated with maturity-onset diabetes of the young and Renal cysts and diabetes syndrome. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics' Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient's phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.