Comprehensive Short Stature Syndrome Panel

Updated
Summary
  • Is a 98 gene panel that includes assessment of non-coding variants.
  • Is ideal for patients with a clinical suspicion of short stature and associated disorders.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

98

Test code

MA2101

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 Comprehensive Short Stature Syndrome Panel (test code MA2101):

ICD codes

Commonly used ICD-10 code(s) when ordering the Comprehensive Short Stature Syndrome Panel

ICD-10 Disease
Q87.1 3-M syndrome
Q87.1 Seckel syndrome
Q87.1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome)
Q87.1 Jawad syndrome
Q87.1 Short stature and associated syndromes
Q87.1 Microcephalic primordial dwarfism disorders (MOPD)
Q87.1 Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome

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.

The clinical phenotypes of the disorders covered by this panel range in the severity of growth retardation and microcephaly, as well as in the degree of developmental delay, but there can be significant clinical overlap among syndromes. In addition to the disorders covered by the sub-panels, this comprehensive panel covers several other diseases associated with short stature, such as growth delay due to insulin-like growth factor I resistance or IGF1 deficiency (mutations in IGF1R and IGF1), hypothyroidism due to deficient transcription factors involved in pituitary development or function (HESX1, LHX3, LHX4, POU1F1 and PROP1), Rubinstein-Taybi syndrome (CREBBP and EP300), Cornelia de Lange syndrome (NIPBL, RAD21, SMC3, HDAC8 and SMC1A) and different forms of disproportionate short stature. Disproportionate short stature can manifest itself as short-limbed dwarfism or short-trunk dwarfism. Achondroplasia (autosomal dominant, mutations is FGFR3) is the most common form of disproportionate growth retardation, its estimated incidence is at about 1/25,000 live births worldwide. Identification of rare monogenic causes of short stature is critical since the genetic diagnosis may alert the clinician to other medical comorbidities for which the patient is at risk. For example, a male patient with 3-M syndrome will need to be monitored for the development of hypogonadism. Based on genetic studies in children with severe short stature of unknown etiology it has been suggested that monogenic causes of short stature are underdiagnosed in the pediatric endocrine clinic. Factors that increase the likelihood for a monogenic cause of short stature are severe GH deficiency, multiple pituitary hormone deficiency, unequivocal GH insensitivity, small for gestational age without catch-up growth, additional congenital anomalies or dysmorphic features, associated intellectual disability, microcephaly and height below −3 SD.

Genes in the Comprehensive Short Stature Syndrome Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ACTB* Baraitser-Winter syndrome AD 55 60
ACTG1* Deafness, Baraitser-Winter syndrome AD 27 47
AMMECR1 Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis XL 4 5
ARCN1 Rhizomelic short stature with microcephaly, micrognathia, and developmental delay (SRMMD) AD 3 3
ATR Cutaneous telangiectasia and cancer syndrome, Seckel syndrome AD/AR 10 33
B3GAT3#* Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects AR 6 13
BCS1L Bjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial complex III deficiency, nuclear type 1 AR 42 37
BRAF* LEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndrome AD 134 65
CBL Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia AD 24 43
CCDC8 Three M syndrome 3 AR 2 3
CDC45 Meier-Gorlin syndrome 7 AR 10 19
CDC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 2 2
CDT1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 6 12
CENPJ Seckel syndrome, Microcephaly AR 34 9
CEP152 Seckel syndrome, Microcephaly AR 20 20
CEP63 Seckel syndrome AR 7 2
COL27A1 Steel syndrome AR 7 7
CREBBP Rubinstein-Taybi syndrome AD 175 362
CUL7 3-M syndrome, Yakut short stature syndrome AR 26 83
DHCR7 Smith-Lemli-Opitz syndrome AR 88 217
DONSON Microcephaly, short stature, and limb abnormalities (MISSLA), Microcephaly-Micromelia syndrome 10 19
EP300 Rubinstein-Taybi syndrome AD 63 101
FGD1 Aarskog-Scott syndrome, Mental retardation, syndromic XL 29 51
FGFR3 Lacrimoauriculodentodigital syndrome, Muenke syndrome, Crouzon syndrome with acanthosis nigricans, Camptodactyly, tall stature, and hearing loss (CATSHL) syndrome, Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia type 1, Thanatophoric dysplasia type 2, SADDAN AD/AR 54 77
FN1 Glomerulopathy with fibronectin deposits 2 AD 14 25
GH1* Isolated growth hormone deficiency, Kowarski syndrome AD/AR 25 90
GHR Growth hormone insensitivity syndrome (Laron syndrome) AD/AR 35 115
GHRHR Isolated growth hormone deficiency AR 13 51
GHSR Short stature AD/AR 2 12
GLI2 Culler-Jones syndrome AD 29 82
GNAS McCune-Albright syndrome, Progressive osseous heteroplasia, Pseudohypoparathyroidism, Albright hereditary osteodystrophy AD 64 274
HDAC8 Cornelia de Lange syndrome XL 41 50
HESX1 Septooptic dysplasia, Pituitary hormone deficiency, combined AR/AD 15 26
HRAS Costello syndrome, Congenital myopathy with excess of muscle spindles AD 43 31
IDUA Mucopolysaccharidosis AR 105 282
IGF1 Insulin-like growth factor I deficiency AR 4 8
IGF1R Insulin-like growth factor I, resistance AD/AR 12 64
IGFALS Insulin-like growth factor-binding protein, acid-labile subunit, deficiency AR 5 34
INSR Hyperinsulinemic hypoglycemia, familial, Rabson-Mendenhall syndrome, Donohoe syndrome AD/AR 44 190
IRS1 Diabetes mellitus, noninsulin-dependent AD/AR 3 17
KRAS* Noonan syndrome, Cardiofaciocutaneous syndrome AD 63 35
LARP7 Alazami syndrome AR 19 10
LFNG# Spondylocostal dysostosis, autosomal recessive 3 AR 1 5
LHX3 Pituitary hormone deficiency, combined AR 9 16
LHX4 Pituitary hormone deficiency, combined AD 10 23
LZTR1 Schwannomatosis, Noonan syndrome AD/AR 34 71
MAP2K1 Cardiofaciocutaneous syndrome AD 45 23
MAP2K2 Cardiofaciocutaneous syndrome AD 21 35
NIPBL Cornelia de Lange syndrome AD 311 425
NOTCH2* Alagille syndrome, Hajdu-Cheney syndrome AD 37 70
NRAS Noonan syndrome AD 31 14
OBSL1 3-M syndrome AR 13 33
ORC1 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 9 10
ORC4 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 24 6
ORC6 Meier-Gorlin syndrome (Ear-patella-short stature syndrome) AR 7 6
OSGEP Galloway-Mowat syndrome AR 11 17
OTX2 Microphthalmia, syndromic, Pituitary hormone deficiency, combined, Retinal dystrophy, early-onset, and pituitary dysfunction AD 23 73
PCNT Microcephalic osteodysplastic primordial dwarfism AR 49 88
PISD AR
PITX2 Axenfeld-Rieger syndrome, Ring dermoid of cornea, Iridogoniodysgenesis, Peters anomaly AD 23 101
POC1A Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis (SOFT syndrome) AR 4 8
POP1 Anauxetic dysplasia 2 AR 5 6
POU1F1 Pituitary hormone deficiency, combined AR 20 41
PPP3CA Epilepitic encephalopathy AD 8 11
PRMT7 Short stature, brachydactyly, intellectual developmental disability, and seizures (SBIDDS) AR 10 11
PROP1 Pituitary hormone deficiency, combined AR 33 37
PTPN11 Noonan syndrome, Metachondromatosis AD 135 140
PUF60 Short stature, Microcephaly AD 24 30
RAD21* Cornelia de Lange syndrome 4 AD 14 11
RAF1 LEOPARD syndrome, Noonan syndrome, Dilated cardiomyopathy (DCM) AD 45 53
RALA* Intellectual disability AD 1
RASA2 Noonan syndrome AD 1 3
RBBP8 Seckel syndrome, Jawad syndrome AR 6 6
RIT1 Noonan syndrome AD 23 26
RNU4ATAC Roifman syndrome, Microcephalic osteodysplastic primordial dwarfism type 1, Microcephalic osteodysplastic primordial dwarfism type 3 AR 15 24
RRAS Noonan-syndrome like phenotype AD/AR 2
RTTN Microcephaly, short stature, and polymicrogyria with or without seizures AR 16 16
SGMS2 Osteoporosis and osteoporotic fractures, Skeletal dysplasia and disorders AD
SHOC2 Noonan-like syndrome with loose anagen hair AD 2 4
SHOX#* Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Short stature XL/PAR 25 431
SMARCA2 Nicolaides-Baraitser syndrome AD 41 73
SMARCE1 Coffin-Siris syndrome AD 14 12
SMC1A Cornelia de Lange syndrome XL 73 87
SMC3 Cornelia de Lange syndrome AD 25 21
SOS1 Noonan syndrome AD 44 71
SOX11 Mental retardation, autosomal dominant 27 AD 11 14
SOX2* Microphthalmia, syndromic AD 34 104
SOX3 Panhypopituitarism XL 4 26
SRCAP Floating-Harbor syndrome AD 16 43
STAT5B* Growth hormone insensitivity with immunodeficiency AR 9 13
TALDO1 Transaldolase deficiency AR 6 10
TBX19 Adrenocorticotropic hormone deficiency AR 12 27
TBX2 AD 1 12
TBX3 Ulnar-Mammary syndrome AD 6 20
TOP3A 8
TRIM37 Mulibrey nanism AR 19 23
TRMT10A Microcephaly, short stature, and impaired glucose metabolism 1 AR 2 7
XRCC4 Short stature, microcephaly, and endocrine dysfunction AR 9 10

* 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 Comprehensive Short Stature Syndrome Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
BCS1L Chr2:219524871 c.-147A>G NM_004328.4
BCS1L Chr2:219525123 c.-50+155T>A NM_004328.4 rs386833855
CEP152 Chr15:49059406 c.2148-17G>A NM_001194998.1 rs751691427
CREBBP Chr16:3788684 c.4281-11C>G NM_004380.2 rs587783493
CUL7 Chr6:43010511 c.3897+29G>A NM_001168370.1
DONSON Chr21:34955994 c.786-22A>G NM_017613.3 rs1135401960
EP300 Chr22:41537040 c.1879-12A>G NM_001429.3
FGD1 ChrX:54476768 c.2016-35delA NM_004463.2
GH1 Chr17:61995330 c.291+29_291+46delGATGGGGGAGACCTGTAG NM_000515.3
GH1 Chr17:61995349 c.291+28G>A NM_000515.3 rs863223306
GH1 Chr17:61996359 c.-223C>T NM_000515.3 rs41295015
GHR Chr5:42689204 c.287+83G>T NM_001242399.2
GHR Chr5:42700896 c.639+792A>G NM_001242399.2
GHR Chr5:42701904 c.639+1800A>G NM_001242399.2
GHRHR Chr7:31003560 c.-124A>C NM_000823.3
GNAS Chr20:57478716 c.2242-11A>G NM_080425.2
LHX4 Chr1:180243784 c.*70G>A NM_033343.3
LZTR1 Chr22:21336623 c.-38T>A NM_006767.3
LZTR1 Chr22:21350968 c.2220-17C>A NM_006767.3 rs1249726034
NIPBL Chr5:36877039 c.-321_-320delCCinsA NM_133433.3 rs724159980
NIPBL Chr5:36877266 c.-94C>T NM_133433.3
NIPBL Chr5:36953718 c.-79-2A>G NM_133433.3
NIPBL Chr5:37022138 c.5329-15A>G NM_133433.3 rs587783968
NIPBL Chr5:37026318 c.5710-13_5710-12delCTinsAA NM_133433.3
OSGEP Chr14:20920111 c.411+12_411+22delGCTCTACCCACinsTAAATAGAG NM_017807.3
PITX2 Chr4:111538758 c.*520_*522delTAT NM_000325.5 rs561702585,rs775662096
PITX2 Chr4:111539855 c.412-11A>G NM_000325.5
PITX2 Chr4:111559138 c.-1214_-1213delAT NM_153426.2
PROP1 Chr5:177420059 c.343-11C>G NM_006261.4
PTPN11 Chr12:112915602 c.934-59T>A NM_002834.3
RBBP8 Chr18:20581745 c.2287+53T>G NM_002894.2
RTTN Chr18:67727297 c.4748-19T>A NM_173630.3
RTTN Chr18:67815044 c.2309+1093G>A NM_173630.3
SHOX ChrX:585123 c.-645_-644insGTT NM_000451.3 rs199946685
SHOX ChrX:585124 c.-645_-644insGTT NM_000451.3
SHOX ChrX:591198 c.-432-3C>A NM_000451.3
SHOX ChrX:591568 c.-65C>A NM_000451.3
TBX2 Chr17:59476302 c.-1236G>C NM_005994.3
TBX2 Chr17:59477201 c.-337C>T NM_005994.3
TBX2 Chr17:59477347 c.-191G>A NM_005994.3
TBX2 Chr17:59477352 c.-185delG NM_005994.3
TBX2 Chr17:59477371 c.-167G>A NM_005994.3
TBX3 Chr12:115122148 NM_016569.3
TRIM37 Chr17:57106096 c.1949-12A>G NM_015294.3
XRCC4 Chr5:82400728 c.-10-1G>T NM_022406.2 rs869320678

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: B3GAT3 (NM_001288722:5), SHOX (NM_006883:6). 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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