Severe Combined Immunodeficiency Panel

Updated
Summary
  • Is a 80 gene panel that includes assessment of non-coding variants.
  • Is ideal for patients with a clinical suspicion of combined immunodeficiencies. The genes on this panel are included in the Primary Immunodeficiency Panel.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

80

Test code

IM0101

Panel size

Large

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 Severe Combined Immunodeficiency Panel (test code IM0101):

ICD codes

Commonly used ICD-10 code(s) when ordering the Severe Combined Immunodeficiency Panel

ICD-10 Disease
D82.0 Wiskott-Aldrich syndrome
D81.9 Combined immunodeficiencies

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.

Severe combined immunedeficiencies (SCIDs) are a group of primary immunodeficiencies characterized by specific mutations in genes of T and B-lymphocyte systems and leading to little or no immune response. Different subtypes of SCIDs are characterized and subdivided by the presence of circulating T and B cells. T cells are absent or markedly decreased in the most types, but levels of B cells vary. In addition, both of these disease subgroups (T-B+ and T-B-) can occur with or without NK cells. Patients with SCID are susceptible to recurrent infections that can be fatal. The worldwide prevalence of SCID is estimated to be at least 1:100,000 births, while some genetically more homogenous populations may show markedly increased numbers. Mutations in IL2RG are the most common reason for SCIDs, explaining approximately 50% of all cases and close to 100% of X-linked cases.

Genes in the Severe Combined Immunodeficiency Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ADA Severe combined immunodeficiency due to adenosine deaminase deficiency AR 49 93
AK2 Reticular dysgenesis AR 14 17
ATM Breast cancer, Ataxia-Telangiectasia AD/AR 1047 1109
BCL11B Immunodeficiency 49 AD 8 12
BLM Bloom syndrome AR 152 119
CARD11 B-cell expansion with NFKB and T-cell anergy, Immunodeficiency AD/AR 12 9
CD247 Immunodeficiency AR 8 4
CD27 Lymphoproliferative syndrome AR 4 8
CD3D Immunodeficiency AR 3 5
CD3E Immunodeficiency AR 4 7
CD3G Immunodeficiency AR 5 3
CD40 Immunodeficiency with Hyper-IgM AR 5 10
CD40LG Immunodeficiency, with hyper-IgM XL 35 231
CD8A CD8 deficiency AR 1 1
CIITA Bare lymphocyte syndrome AR 9 15
CORO1A#* Immunodeficiency AR 41 6
DCLRE1C* Omenn syndrome, Severe combined immunodeficiency with sensitivity to ionizing radiation AR 18 89
DNMT3B Immunodeficiency-centromeric instability-facial anomalies syndrome AR 14 47
DOCK8 Hyper-IgE recurrent infection syndrome, Mental retardation, autosomal dominant 2 AR 54 168
EPG5 Vici syndrome AR 36 66
FOXN1 T-cell immunodeficiency, congenital alopecia, and nail dystrophy AR 6 6
IFNGR1 Immunodeficiency AD/AR 16 42
IKBKB Immunodeficiency 15 AR 2 7
IL12RB1# Immunodeficiency AR 13 82
IL2RA Interleukin 2 receptor, alpha, deficiency AR 6 6
IL2RG Combined immunodeficiency XL 54 243
IL7R Severe combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positive AR 23 48
IRF8 Immunodeficiency 32A (CD11C-positive/CD1C-positive dendritic cell deficiency), Immunodeficiency 32B (monocyte and dendritic cell deficiency) AD/AR 4 8
ITGB2 Leukocyte adhesion deficiency AR 33 118
ITK Lymphoproliferative syndrome AR 4 11
JAK3 Severe combined immunodeficiency, , T cell-negative, B cell-positive, natural killer cell-negative AR 30 66
LAT Immunodeficiency 52 AR 2 18
LCK Immunodeficiency AR 2 3
LIG4 Severe combined immunodeficiency with sensitivity to ionizing radiation, LIG4 syndrome AR 18 36
LRBA Common variable immunodeficiency AR 23 64
MAGT1 Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia, Mental retardation, X-linked 95 XL 8 14
MALT1 Immunodeficiency AR 3 5
MAP3K14 Primary immunodeficiency with multifaceted aberrant lymphoid immunity AR 1 2
MSN* Immunodeficiency 50 XL 2 2
NHEJ1 Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation AR 15 16
NSMCE3 Lung disease, immunodeficiency, and chromosome breakage syndrome (LICS) AR 2 2
ORAI1 Immunodeficiency, Myopathy, tubular aggregate, 2 AD/AR 9 13
PARN* Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenita AD/AR 15 29
PGM3 Immunodeficiency 23 AR 14 15
PIK3CD* Immunodeficiency AD 6 12
PMS2* Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposis AD/AR 319 342
PNP Purine nucleoside phosphorylase deficiency AR 11 33
POLE Colorectal cancer, Facial dysmorphism, immunodeficiency, livedo, and short stature syndrome (FILS syndrome) AD/AR 8 70
POLE2 Combined immunodeficiency AR 3
PRKDC Immunodeficiency AR 6 9
PTPRC Severe combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positive AR 4 5
RAC2 Neutrophil immunodeficiency syndrome AD 2 3
RAG1 Omenn syndrome, Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity, T cell-negative, B cell-negative, natural killer cell-positive severe combined immunodeficiency, Combined cellular and humoral immune defects with granulomas AR 47 184
RAG2 Omenn syndrome, Combined cellular and humoral immune defects with granulomas AR 28 79
RFX5 Bare lymphocyte syndrome AR 4 10
RFXANK MHC class II deficiency AR 8 16
RFXAP Bare lymphocyte syndrome AR 6 9
RHOH T-cell immunodeficiency with epidermodysplasia verruciformis AD/AR 1
RMRP Cartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasia AR 87 123
RTEL1 Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenita AD/AR 58 51
SH2D1A Lymphoproliferative syndrome XL 21 129
SMARCAL1 Schimke immunoosseous dysplasia AR 20 88
SP110 Hepatic venoocclusive disease with immunodeficiency AR 8 8
SPINK5 Netherton syndrome AR 29 85
STAT1 Immunodeficiency AD/AR 39 122
STAT2 Immunodeficiency AR 3 6
STAT3 Hyper-IgE recurrent infection syndrome, Autoimmune disease, multisystem, infantile onset AD 47 152
STAT5B* Growth hormone insensitivity with immunodeficiency AR 9 13
STIM1 Stormorken syndrome, Immunodeficiency, Myopathy, tubular aggregate 1 AD/AR 13 24
STK4 T-cell immunodeficiency syndrome, recurrent infections, autoimmunity, AR 3 7
TAP1 Bare lymphocyte syndrome AR 1 7
TAP2 Bare lymphocyte syndrome AR 4 8
TAPBP Bare lymphocyte syndrome AR 1 2
TBX1 Conotruncal anomaly face syndrome AD 17 72
TFRC Immunodeficiency 46 AR 8 2
TNFRSF4 Immunodeficiency AR 1 1
TYK2 Immunodeficiency AR 9 9
UNC119 Immunodeficiency, Cone-rod dystrophy 2 AD 1 5
WAS Neutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndrome XL 57 439
ZAP70 Selective T-cell defect AR 15 29

* 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 Severe Combined Immunodeficiency Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ADA Chr20:43248503 c.1079-15T>A NM_000022.2 rs387906268
ADA Chr20:43249076 c.976-34G>A NM_000022.2
ATM Chr11:108093770 c.-174A>G NM_000051.3
ATM Chr11:108094508 c.-31+595G>A NM_000051.3
ATM Chr11:108098321 c.-30-1G>T NM_000051.3 rs869312754
ATM Chr11:108138753 c.2639-384A>G NM_000051.3
ATM Chr11:108141209 c.2839-579_2839-576delAAGT NM_000051.3
ATM Chr11:108151710 c.3403-12T>A NM_000051.3 rs201370733
ATM Chr11:108158168 c.3994-159A>G NM_000051.3 rs864622543
ATM Chr11:108164028 c.4612-12A>G NM_000051.3
ATM Chr11:108179837 c.5763-1050A>G NM_000051.3 rs774925473
ATM Chr11:108214779 c.8418+681A>G NM_000051.3 rs748635985
CD40LG ChrX:135736498 c.289-32_289-25delAAAATGAC NM_000074.2
CD40LG ChrX:135736517 c.289-15T>A NM_000074.2
CD40LG ChrX:135737600 c.347-915A>T NM_000074.2
DNMT3B Chr20:31395557 c.2421-11G>A NM_006892.3 rs547940069
DOCK8 Chr9:317025 c.742-18C>G NM_203447.3 rs112373444
DOCK8 Chr9:317028 c.742-15T>G NM_203447.3 rs111627162
DOCK8 Chr9:368196 c.1797+61A>C NM_203447.3 rs786205596
IL2RG ChrX:70327277 c.*307_*308delAA NM_000206.2
IL2RG ChrX:70327278 c.*308A>G NM_000206.2
IL2RG ChrX:70330553 c.270-15A>G NM_000206.2
IL2RG ChrX:70331494 c.-105C>T NM_000206.2
IL7R Chr5:35867853 c.379+288G>A NM_002185.3
ITGB2 Chr21:46320404 c.742-14C>A NM_000211.3 rs183204825
ITGB2 Chr21:46321660 c.500-12T>G NM_000211.3
JAK3 Chr19:17943239 c.2680+89G>A NM_000215.3
JAK3 Chr19:17946035 c.1915-11G>A NM_000215.3
PARN Chr16:14724045 c.-165+2C>T NM_001134477.2
PMS2 Chr7:6027263 c.1145-31_1145-13delCTGACCCTCTTCTCCGTCC NM_000535.5 rs751973268
PMS2 Chr7:6048599 c.23+21_23+28delTCCGGTGT NM_000535.5
PNP Chr14:20942914 c.286-18G>A NM_000270.3
POLE Chr12:133249181 c.1686+32C>G NM_006231.2 rs762985435
RAG2 Chr11:36619652 c.-28G>C NM_000536.3
RFXANK Chr19:19307761 c.188-11C>T NM_003721.3 rs201545133
RMRP Chr9:35658026 NR_003051.3 rs781730798
RMRP Chr9:35658026 NR_003051.3
RMRP Chr9:35658026 NR_003051.3
RMRP Chr9:35658026 NR_003051.3
RMRP Chr9:35658027 NR_003051.3
RMRP Chr9:35658027 NR_003051.3
RMRP Chr9:35658027 NR_003051.3
RMRP Chr9:35658027 NR_003051.3 rs727502775
RMRP Chr9:35658027 NR_003051.3
RMRP Chr9:35658028 NR_003051.3
RMRP Chr9:35658028 NR_003051.3
RMRP Chr9:35658029 NR_003051.3
RMRP Chr9:35658029 NR_003051.3
RMRP Chr9:35658032 NR_003051.3
SH2D1A ChrX:123499593 c.138-17_138-11delAGTTTAT NM_002351.4
SPINK5 Chr5:147465956 c.283-12T>A NM_006846.3
SPINK5 Chr5:147484503 c.1431-12G>A NM_006846.3 rs368134354
SPINK5 Chr5:147491511 c.1820+53G>A NM_006846.3 rs754599628
TBX1 Chr22:19743578 c.-777C>T NM_080647.1
TBX1 Chr22:19743735 c.-620A>C NM_080647.1 rs536892777
WAS ChrX:48547690 c.1339-19_1339-11delTGATCCCTGinsATCTGCAGACC NM_000377.2
ZAP70 Chr2:98349927 c.838-80G>A NM_001079.3 rs113994173
ZAP70 Chr2:98354447 c.1624-11G>A NM_001079.3 rs730880318

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

The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: CORO1A (NM_007074:11), IL12RB1 (NM_153701:10). Genes with suboptimal coverage in our assay are marked with number sign (#) and 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. Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. 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 99.2% (7,745/7,806) >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% (25/25)
     
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 ACMG guideline 2015.

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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