Hypoglycemia, Hyperinsulinism and Ketone Metabolism Panel

Summary
  • Is a 50 gene panel that includes assessment of non-coding variants.
  • Is ideal for patients with a clinical suspicion of hypoglycemia and familial hyperinsulinism. The genes on this panel are included in the Comprehensive Metabolism Panel.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

50

Test code

ME0601

Panel size

Small

CPT code *
81443(1)
* The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.

Summary

The Blueprint Genetics Hypoglycemia, Hyperinsulinism and Ketone Metabolism Panel (test code ME0601):

ICD codes

Commonly used ICD-10 code(s) when ordering the Hypoglycemia, Hyperinsulinism and Ketone Metabolism Panel

ICD-10 Disease
E16.1 Familial hyperinsulinism
E11.9 MODY maturity onset diabetes of the young

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Please see Sample Requirements for accepted saliva kits)

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

We do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. In addition, if the patient is affected with a hematological malignancy, DNA extracted from a non-hematological source (e.g. skin fibroblasts) is strongly recommended.

Please note that, in rare cases, mitochondrial genome (mtDNA) variants may not be detectable in blood or saliva in which case DNA extracted from post-mitotic tissue such as skeletal muscle may be a better option.

Read more about our sample requirements here.

Familial hyperinsulinism (FHI) is characterized by hypoglycemia that can have an onset neonatally or later during childhood. The disease presentation can vary considerably even within one family. It can present as severe with a very low glucose concentration or with variable and milder hypoglycemia. The clinical utility of this panel for familial hyperinsulinism is 50-60%. Most of the patients with familial hyperinsulinism have a mutated ABCC8 gene, while mutations in KCNJ11, GLUD1 and HFN4A have each been found in approximately 5% of patients. Congenital isolated hyperinsulinism is the most common cause of severe and persistent hypoglycemia in neonatal period. The prevalence has been estimated at 1:50,000 live births, with much higher numbers in certain more homogenous populations. Infants of diabetic mothers may present with a clinical picture identical to that of FHI and this panel has differential diagnostic power to diagnose cases with genetic causes of transient hypoglycemia in newborns. This panel also includes the Glycogen Storage Disorder Panel genes for differential diagnostic purposes, since hepatomegaly due to glycogen storage disorder might not be visible in the newborn period. Furthermore, the panel includes genes relevant in additional related phenotypes such as maturity onset diabetes of the young (MODY) or exercise-induced hyperinsulinism. Insulinoma and drug-induced hypoglycemia should also be considered in later-onset hyperinsulinism phenotypes.

Genes in the Hypoglycemia, Hyperinsulinism and Ketone Metabolism Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCC8 Hyperinsulinemic hypoglycemia, Diabetes, permanent neonatal, Hypoglycemia, leucine-induced, Diabetes mellitus, transient neonatal, Pulmonary arterial hypertension (PAH) AD/AR 170 641
ACAT1 Alpha-methylacetoacetic aciduria AR 31 95
ACSF3 Combined malonic and methylmalonic aciduria AR 18 22
AGL Glycogen storage disease AR 142 245
ALDOA Glycogen storage disease AR 3 8
ALDOB Fructose intolerance, hereditary AR 41 67
ENO3 Glycogen storage disease AR 3 6
EPM2A Epilepsy, progressive myoclonic AR 17 77
FBP1 Fructose-1,6-bisphosphatase deficiency AR 25 44
G6PC Glycogen storage disease AR 46 117
GAA Glycogen storage disease AR 193 573
GBE1 Glycogen storage disease AR 36 70
GCK Hyperinsulinemic hypoglycemia, familial, Diabetes mellitus, permanent neonatal, Maturity-onset diabetes of the young, type 2 AD/AR 178 837
GLUD1* Hyperammonemia-hyperinsulinism, Hyperinsulinemic hypoglycemia AD/AR 14 38
GYG1 Glycogen storage disease, Polyglucosan body myopathy 2 AR 9 16
GYS1 Glycogen storage disease AR 8 5
GYS2 Glycogen storage disease AR 20 23
HADH 3-hydroxyacyl-CoA dehydrogenase deficiency AR 10 26
HMGCL 3-hydroxy-3-methylglutaryl-CoA lyase deficiency AR 24 60
HMGCS2 3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency AR 9 30
HNF1A Maturity onset diabetes of the young, Renal cell carcinoma, nonpapillary clear cell, Liver adenomatosis AD 78 528
HNF4A Congenital hyperinsulinism, diazoxide-responsive, Maturity onset diabetes of the young, Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young AD 32 147
INSR Hyperinsulinemic hypoglycemia, familial, Rabson-Mendenhall syndrome, Donohoe syndrome AD/AR 44 190
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 63 178
LAMP2 Danon disease XL 62 101
LDHA Glycogen storage disease AR 1 9
MPV17 Mitochondrial DNA depletion syndrome AR 35 50
NHLRC1 Epilepsy, progressive myoclonic AR 14 70
OXCT1 Succinyl CoA:3-oxoacid CoA transferase deficiency AR 7 33
PC Pyruvate carboxylase deficiency AR 32 41
PCK1 Phosphoenolpyruvate carboxykinase 1 deficiency AD/AR 2 3
PDX1 Pancreatic agenesis, Neonatal diabetes mellitus, Maturity-onset diabetes of the young, type 4, Lactic acidemia due to PDX1 deficiency AD/AR 10 28
PFKM Glycogen storage disease AR 12 26
PGAM2 Glycogen storage disease AR 4 11
PGK1 Phosphoglycerate kinase 1 deficiency XL 16 26
PGM1 Congenital disorder of glycosylation AR 11 35
PHKA1 Glycogen storage disease XL 9 8
PHKA2 Glycogen storage disease XL 36 114
PHKB Glycogen storage disease AR 9 26
PHKG2 Glycogen storage disease AR 12 33
PRKAG2 Hypertrophic cardiomyopathy (HCM), Wolff-Parkinson-White syndrome, Glycogen storage disease of heart, lethal congenital AD 19 57
PRKAG3 Increased glyogen content in skeletal muscle AD 1 1
PTF1A Pancreatic and cerebellar agenesis, Pancreatic agenesis 2 AR 4 16
PYGL Glycogen storage disease AR 21 44
PYGM Glycogen storage disease AR 77 168
RBCK1 Polyglucosan body myopathy AR 11 14
SLC16A1 Hyperinsulinemic hypoglycemia, familial, Erythrocyte lactate transporter defect, Monocarboxylate transporter 1 deficiency, Myoclonic-atonic epilepsy AD/AR 12 14
SLC2A2 Glycogen storage disease, Fanconi-Bickel syndrome, Neonatal diabetes mellitus AR 24 73
SLC37A4 Glycogen storage disease AR 49 113
UCP2 Hyperinsulinism AD/AR 7

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads.

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), 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 Mitomap databases.

Non-coding variants covered by Hypoglycemia, Hyperinsulinism and Ketone Metabolism Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ABCC8 Chr11:17415959 c.4412-13G>A NM_000352.3 rs1008906426
ABCC8 Chr11:17427028 c.3399+13G>A NM_000352.3 rs182340196
ABCC8 Chr11:17449501 c.2041-12C>A NM_000352.3
ABCC8 Chr11:17449510 c.2041-21G>A NM_000352.3 rs746714109
ABCC8 Chr11:17449514 c.2041-25G>A NM_000352.3
ABCC8 Chr11:17452526 c.1672-20A>G NM_000352.3
ABCC8 Chr11:17465872 c.1333-1013A>G NM_000352.3
ABCC8 Chr11:17470268 c.1177-53_1177-51delGTG NM_000352.3 rs1271038564
ABCC8 Chr11:17498513 c.-190C>G NM_000352.3
ACAT1 Chr11:108004534 c.121-13T>A NM_000019.3
AGL Chr1:100381954 c.4260-12A>G NM_000028.2 rs369973784
ALDOB Chr9:104183575 c.*516T>A NM_000035.3
ALDOB Chr9:104197990 c.-11+1G>C NM_000035.3 rs181639417
ALDOB Chr9:104198194 NM_000035.3 rs185972191
G6PC Chr17:41059684 c.446+39G>A NM_000151.3
G6PC Chr17:41059687 c.446+42G>A NM_000151.3
GAA Chr17:78078341 c.-32-13T>A NM_000152.3
GAA Chr17:78078341 c.-32-13T>G NM_000152.3 rs386834236
GAA Chr17:78078351 c.-32-3C>A/G NM_000152.3
GAA Chr17:78078352 c.-32-2A>G NM_000152.3
GAA Chr17:78078353 c.-32-1G>C NM_000152.3
GAA Chr17:78078369 c.-17C>T NM_000152.3
GAA Chr17:78082266 c.1076-22T>G NM_000152.3 rs762260678
GAA Chr17:78090422 c.2190-345A>G NM_000152.3
GAA Chr17:78092432 c.2647-20T>G NM_000152.3
GBE1 Chr3:81542964 c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT NM_000158.3 rs869320698
GCK Chr7:44186044 c.1022+18G>A NM_033507.1 rs150914617
GCK Chr7:44193073 c.49-15_49-11delCCCCTinsGGGAGGG NM_033507.1
GCK Chr7:44229009 c.-457C>T NM_000162.3 rs548039601
GCK Chr7:44229109 c.-557G>C NM_000162.3
GYG1 Chr3:148717967 c.481+3276C>G NM_004130.3
HADH Chr4:108945190 c.636+471G>T NM_001184705.2 rs786200932
HADH Chr4:108948955 c.709+39C>G NM_001184705.2
HNF1A Chr12:121416034 c.-538G>C NM_000545.5
HNF1A Chr12:121416110 c.-462G>A NM_000545.5
HNF1A Chr12:121416281 c.-291T>C NM_000545.5 rs534474388
HNF1A Chr12:121416285 c.-287G>A NM_000545.5
HNF1A Chr12:121416285 NM_000545.5
HNF1A Chr12:121416289 c.-283A>C NM_000545.5
HNF1A Chr12:121416314 c.-258A>G NM_000545.5 rs756136537
HNF1A Chr12:121416354 c.-218T>C NM_000545.5
HNF1A Chr12:121416385 c.-187C>A/T NM_000545.5
HNF1A Chr12:121416385 NM_000545.5
HNF1A Chr12:121416385 NM_000545.5 rs970766228
HNF1A Chr12:121416391 NM_000545.5
HNF1A Chr12:121416437 NM_000545.5
HNF1A Chr12:121416446 NM_000545.5 rs780586155
HNF1A Chr12:121416453 c.-119G>A NM_000545.5 rs371945966
HNF1A Chr12:121416475 c.-97T>G NM_000545.5
HNF1A Chr12:121416508 NM_000545.5
HNF4A Chr20:42984253 c.-192C>G NM_175914.4
HNF4A Chr20:42984264 c.-181G>A NM_175914.4
HNF4A Chr20:42984271 c.-174T>C NM_175914.4
HNF4A Chr20:42984276 c.-169C>T NM_175914.4
HNF4A Chr20:42984299 c.-146T>C NM_175914.4
HNF4A Chr20:42984309 c.-136A>G NM_175914.4
HNF4A Chr20:43036000 c.291-21A>G NM_000457.4
KCNJ11 Chr11:17409692 c.-54C>T NM_000525.3
KCNJ11 Chr11:17409772 c.-134G>T NM_000525.3 rs387906398
PC Chr11:66620883 c.1369-29A>G NM_000920.3
PFKM Chr12:48535459 c.1626-64A>G NM_001166686.1
PGK1 ChrX:77381262 c.1214-25T>G NM_000291.3
PGM1 Chr1:64113966 c.1199-222G>T NM_001172818.1
PHKG2 Chr16:30762416 c.96-11G>A NM_000294.2 rs751600886
PTF1A Chr10:23508305 c.*25470A>G NM_178161.2
PTF1A Chr10:23508363 c.*25528A>G NM_178161.2
PTF1A Chr10:23508365 c.*25530A>G NM_178161.2
PTF1A Chr10:23508437 c.*25602A>G NM_178161.2
PTF1A Chr10:23508442 c.*25607A>G NM_178161.2
PTF1A Chr10:23508446 c.*25611A>C NM_178161.2
PYGM Chr11:64523631 c.661-601G>A NM_005609.2
PYGM Chr11:64525847 c.425-26A>G NM_005609.2 rs764313717
SLC16A1 Chr1:113498814 c.-202G>A NM_003051.3 rs387906403
SLC16A1 Chr1:113499002 c.-391_-390insACGCCGGTCACGTGGCGGGGTGGGG NM_003051.3 rs606231172
SLC2A2 Chr3:170745041 c.-582A>C NM_000340.1

Test Strengths

The strengths of this test include:
  • CAP accredited laboratory
  • 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
  • Some of the panels include the whole mitochondrial genome (please see the Panel Content section)
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publicly available analytic validation demonstrating complete details of test performance
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section)
  • Our rigorous 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

Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Some of the panels include the whole mitochondrial genome but not all (please see the Panel Content section)
  • 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 in nuclear genes (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Low level heteroplasmy in mtDNA (>90% are detected at 5% level)
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis.

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 genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).

Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.

Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.89% (99,153/99,266) >99.9999%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.9% (7,563/7,806) >99.9999%
11-50 bps 99.13% (2,524/2,546) >99.9999%
Copy number variants (exon level dels/dups)
1 exon level deletion (heterozygous) 100% (20/20) NA
1 exon level deletion (homozygous) 100% (5/5) NA
1 exon level deletion (het or homo) 100% (25/25) NA
2-7 exon level deletion (het or homo) 100% (44/44) NA
1-9 exon level duplication (het or homo) 75% (6/8) NA
Simulated CNV detection
5 exons level deletion/duplication 98.7% 100.00%
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
     
The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics
     
Mean sequencing depth 143X
Nucleotides with >20x sequencing coverage (%) 99.86%


Performance of Blueprint Genetics Mitochondrial Sequencing Assay.

Sensitivity % Specificity %
ANALYTIC VALIDATION (NA samples; n=4)
Single nucleotide variants
Heteroplasmic (45-100%) 100.0% (50/50) 100.0%
Heteroplasmic (35-45%) 100.0% (87/87) 100.0%
Heteroplasmic (25-35%) 100.0% (73/73) 100.0%
Heteroplasmic (15-25%) 100.0% (77/77) 100.0%
Heteroplasmic (10-15%) 100.0% (74/74) 100.0%
Heteroplasmic (5-10%) 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 50.0% (2/4) 100.0%
CLINICAL VALIDATION (n=76 samples)
All types
Single nucleotide variants n=2026 SNVs
Heteroplasmic (45-100%) 100.0% (1940/1940) 100.0%
Heteroplasmic (35-45%) 100.0% (4/4) 100.0%
Heteroplasmic (25-35%) 100.0% (3/3) 100.0%
Heteroplasmic (15-25%) 100.0% (3/3) 100.0%
Heteroplasmic (10-15%) 100.0% (9/9) 100.0%
Heteroplasmic (5-10%) 92.3% (12/13) 99.98%
Heteroplasmic (<5%) 88.9% (48/54) 99.93%
Insertions and deletions by sequence analysis n=40 indels
Heteroplasmic (45-100%) 1-10bp 100.0% (32/32) 100.0%
Heteroplasmic (5-45%) 1-10bp 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 1-10bp 100.0% (5/5) 99,997%
SIMULATION DATA /(mitomap mutations)
Insertions, and deletions 1-24 bps by sequence analysis; n=17
Homoplasmic (100%) 1-24bp 100.0% (17/17) 99.98%
Heteroplasmic (50%) 100.0% (17/17) 99.99%
Heteroplasmic (25%) 100.0% (17/17) 100.0%
Heteroplasmic (20%) 100.0% (17/17) 100.0%
Heteroplasmic (15%) 100.0% (17/17) 100.0%
Heteroplasmic (10%) 94.1% (16/17) 100.0%
Heteroplasmic (5%) 94.1% (16/17) 100.0%
Copy number variants (separate artifical mutations; n=1500)
Homoplasmic (100%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (50%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (30%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (20%) 500 bp, 1kb, 5 kb 99.7% 100.0%
Heteroplasmic (10%) 500 bp, 1kb, 5 kb 99.0% 100.0%
The performance presented above reached by following coverage metrics at assay level (n=66)
Mean of medians Median of medians
Mean sequencing depth MQ0 (clinical) 18224X 17366X
Nucleotides with >1000x MQ0 sequencing coverage (%) (clinical) 100%
rho zero cell line (=no mtDNA), mean sequencing depth 12X

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 and regulatory 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. If the test includes the mitochondrial genome the target region gene list contains the mitochondrial genes. 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 including, 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, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with suboptimal coverage (<20X for nuclear genes and <1000X for mtDNA) if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the 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 is orthogonal confirmation. Sequence and copy number variants classified as pathogenic, likely pathogenic and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing by orthogonal methods such as qPCR/ddPCR when they do not meet our stringent NGS quality metrics for a true positive call.

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, abstracts and variant databases used to help ordering providers 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. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. 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.

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