Comprehensive Monogenic Diabetes Panel
Test code: EN0401
The Blueprint Genetics Comprehensive Monogenic Diabetes Panel is a 25 gene test for genetic diagnostics of patients with clinical suspicion of monogenic diabetes or neonatal diabetes mellitus.
The panel covers genes associated with autosomal recessive and autosomal dominant forms of the disease.
About Monogenic Diabetes
Monogenic diabetes consists of a heterogenous group of diabetes types that are caused by mutations in single genes, estimated to represent as much as 1-2% of all cases of diabetes mellitus (DM). The main phenotypes suggestive of an underlying monogenic cause include neonatal diabetes mellitus (NDM), maturity-onset diabetes of the young (MODY) and other very rare diabetes-associated syndromes. Permanent neonatal diabetes mellitus (PNDM) is a monogenic form of neonatal diabetes characterized by persistent hyperglycemia within the first 12 months of life in general (median age of onset of nine weeks), requiring continuous insulin treatment. Initial clinical manifestations include hyperglycemia, glycosuria, intrauterine growth retardation, osmotic polyuria, severe dehydration, and failure to gain weight. Transient form of neonatal diabetes mellitus (TNDM) typically resolves by 18 months of age. Many patients display some degree of developmental coordination disorder. The incidence of NDM is estimated to be 1:95,000 to 1:150,000 live births. About 50% of NDM cases are permanent (PNDM) and 50% transient (TNDM). The condition has been reported in all ethnic groups and affects male and female infants equally. Neonatal diabetes, most commonly caused by mutations in the KCNJ11 (34%), ABCC8 (24%), INS (13%) and GCK (4%) genes. Clinical manifestations differ depending on the underlying genetic defect. In KCNJ11 and ABCC8-related cases, patients usually present before three months of age with symptomatic hyperglycemia, and often ketoacidosis. Approximately 25% of patients with mutations in the KCNJ11 gene have related neurological findings, including developmental delay and epilepsy (DEND syndrome) or a milder form of DEND without seizures and with less severe developmental delay (intermediate DEND). In INS-related cases, patients present with marked hyperglycemia or diabetic ketoacidosis on average at nine weeks, but some at a much later age. GCK-related PNDM patients have permanent insulin-dependent diabetes from the first day of life. Comprehesive Monogenic Diabetes Panel covers MODY, which is described in detail MODY Panel description.
Results in 3-4 weeks.
|ABCC8||Hyperinsulinemic hypoglycemia, Diabetes, permanent neonatal, Hypoglycemia, leucine-induced, Diabetes mellitus, transient neonatal||AD/AR||78||601|
|BLK||Maturity onset diabetes of the young||AD||4||15|
|FOXP3||Immunodysregulation, polyendocrinopathy, and enteropathy||XL||18||83|
|GCK||Hyperinsulinemic hypoglycemia, familial, Diabetes mellitus, permanent neonatal||AD/AR||118||774|
|GLIS3||Diabetes mellitus, neonatal, with congenital hypothyroidism||AR||8||9|
|GLUD1*||Hyperammonemia-hyperinsulinism, Hyperinsulinemic hypoglycemia||AD/AR||14||37|
|HADH||3-hydroxyacyl-CoA dehydrogenase deficiency||AR||8||25|
|HNF1A||Maturity onset diabetes of the young, Renal cell carcinoma, nonpapillary clear cell, Liver adenomatosis||AD||47||505|
|HNF1B||Renal cell carcinoma, nonpapillary chromophobe, Renal cysts and diabetes syndrome||AD||27||194|
|HNF4A||Congenital hyperinsulinism, diazoxide-responsive, Maturity onset diabetes of the young, Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young||AD||19||145|
|INS||Diabetes mellitus, permanent neonatal||AD||32||74|
|INSR||Hyperinsulinemic hypoglycemia, familial, Rabson-Mendenhall syndrome, Donohoe syndrome||AD/AR||35||175|
|KCNJ11||Hyperinsulinemic hypoglycemia, Diabetes, permanent neonatal, Diabetes mellitus, transient neonatal||AD/AR||49||171|
|KLF11||Maturity onset diabetes of the young||AD||1||5|
|NEUROD1||Maturity onset diabetes of the young||AD||3||15|
|NEUROG3||Diarrhea, malabsorptive, congenital||AR||2||9|
|PDX1||Pancreatic agenesis, Neonatal diabetes mellitus||AR||10||29|
|PPARG||Insulin resistance, Lipodystrophy, familial, partial||AD/Digenic (Severe digenic insulin resistance can be due to digenic mutations in PPP1R3A and PPARG)||12||42|
|SLC2A2||Glycogen storage disease, Fanconi-Bickel syndrome, Neonatal diabetes mellitus||AR||15||77|
|SLC16A1||Hyperinsulinemic hypoglycemia, familial, Erythrocyte lactate transporter defect, Monocarboxylate transporter 1 deficiency||AD/AR||11||12|
- * Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.
Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.
Blueprint Genetics offers a comprehensive monogenic diabetes panel that covers classical genes associated with hypoglycemia, unspecified, maturity-onset diabetes of the young, monogenic diabetes and neonatal diabetes mellitus. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.
Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.
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. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).
Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.
In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.
Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.
A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.
We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.
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ICD & CPT codes
Commonly used ICD-10 codes when ordering the Comprehensive Monogenic Diabetes Panel
|P70.2||Neonatal diabetes mellitus|
Accepted sample types
- EDTA blood, min. 1 ml
- Purified DNA, min. 5μg
- 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.