Marfan Syndrome Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: CA0801

The Blueprint Genetics Marfan Syndrome Panel is a 25-gene test for genetic diagnostics of patients with clinical suspicion of Marfan syndrome or other disorder that resembles Marfan syndrome. This Panel covers diseases such as arterial tortuosity syndrome, congenital contractural arachnodactyly, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, Marfan syndrome and Shprintzen-Goldberg syndrome.

Disorders that share phenotypic features with Marfan syndrome are inherited in an autosomal dominant and autosomal recessive manner. Genetic diagnosis has substantial significance for the patient and his family as it forms the basis for genetic counseling and can be used to determine risk of vascular complications and assessment of treatment strategies.

About Marfan Syndrome

The diagnosis of Marfan syndrome can be difficult as many of the features are also identified in normal population, features appear in an age-dependent manner and there is substantial phenotypic variability between the patients. There is also considerable overlap with other connective-tissue disorders such as congenital contractural arachnodactyly (CCA), Loeys-Dietz syndrome (LDS), Ehlers-Danlos syndrome, arterial tortuosity syndrome and Shprintzen-Goldberg syndrome. The Marfan Panel is designed as a genetic diagnostic tool for patients suffering from clinical features of Marfan syndrome. The two major features of Marfan syndrome are vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes and aortic aneurysms and dissection. Aortic aneurysm and dissection can be life threatening. Mitral valve regurgitation is another cardiovascular defect associated with disorder. Individuals with Marfan syndrome are usually tall and slender, have elongated fingers and toes, and have an arm span that exceeds their body height. Other common features include crowded teeth, a long and narrow face, dural ectasia, an abnormal curvature of the spine, and chest abnormalities. The features of Marfan syndrome can become apparent anytime between infancy and adulthood. Depending on the onset and severity of signs and symptoms, Marfan syndrome can be fatal early in life; however, the majority of affected individuals survive into mid- to late adulthood.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Marfan Syndrome Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ADAMTSL4 Ectopia lentis, isolated AR 10 20
CBS Homocystinuria due to cystathionine beta-synthase deficiency AR 69 187
COL1A1 Ehlers-Danlos syndrome, Caffey disease, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 AD 212 929
COL1A2 Ehlers-Danlos syndrome, cardiac valvular form, Osteogenesis imperfecta type 1, Osteogenesis imperfecta type 2, Osteogenesis imperfecta type 3, Osteogenesis imperfecta type 4 AD/AR 118 490
COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1 AD 138 541
COL3A1 Ehlers-Danlos syndrome AD 476 620
COL5A1 Ehlers-Danlos syndrome AD 62 136
COL5A2 Ehlers-Danlos syndrome AD 15 23
COL9A1 Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6) AR 7 5
COL9A2 Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2) AD/AR 7 12
COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 22 81
COL18A1 Knobloch syndrome AR 23 27
FBN1 MASS syndrome, Shprintzen-Goldberg syndrome, Marfan syndrome, Acromicric dysplasia, Geleophysic dysplasia, Weill-Marchesani syndrome AD 711 2070
FBN2 Congenital contractural arachnodactyly (Beals syndrome) AD 35 87
MED12 Ohdo syndrome, Mental retardation, with Marfanoid habitus, FG syndrome, Opitz-Kaveggia syndrome, Lujan-Fryns syndrome XL 24 26
PLOD1 Ehlers-Danlos syndrome AR 19 37
SKI Shprintzen-Goldberg syndrome AD 16 20
SLC2A10 Arterial tortuosity syndrome AR 22 29
SMAD3 Aneurysms-osteoarthritis syndrome, Loeys-Dietz syndrome AD 35 53
TGFB2 Loeys-Dietz syndrome AD 25 27
TGFB3 Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasia AD 13 19
TGFBR1 Loeys-Dietz syndrome AD 28 68
TGFBR2 Loeys-Dietz syndrome AD 57 132
UPF3B Mental retardation, syndromic XL 8 18
VCAN Wagner disease AD 11 19

*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.

Gene Genomic location HG19 HGVS RefSeq RS-number
COL11A1 Chr1:103491958 c.781-450T>G NM_080629.2 rs587782990
COL1A2 Chr7:94025130 c.70+717A>G NM_000089.3 rs72656354
COL3A1 Chr2:189872183 c.3256-43T>G NM_000090.3 rs587779667
COL5A1 Chr9:137686903 c.2701-25T>G NM_000093.4 rs765079080
TGFB3 Chr14:76425035 c.*495C>T NM_003239.2 rs387906514
TGFB3 Chr14:76447266 c.-30G>A NM_003239.2 rs770828281

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

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
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

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.

Blueprint Genetics offers a comprehensive Marfan Syndrome Panel that covers classical genes associated with aortic anaurysm, ruptured, abdominal aorta, aortic aneurysm, ruptured, thracic aorta, aortic aneurysm, ruptured, unspecific site, aortic aneurysm, thoracic aorta, aortic disection, thorcic aorta, arterial tortuosity syndrome, congenital contractural arachnodactyly, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, Marfan syndrome and Shprintzen-Goldberg syndrome. 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.

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. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. 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.

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.

Find more info in Support

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Extra services

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ICD & CPT codes

CPT codes

SEQ 81410
DEL/DUP 81411


ICD codes

Commonly used ICD-10 codes when ordering the Marfan Syndrome Panel

ICD-10 Disease
Q87.40 Marfan syndrome
Q87.89 Loeys-Dietz syndrome
Q87.89 Shprintzen-Goldberg syndrome
Q79.6 Ehlers-Danlos syndrome
Q87.89 Arterial tortuosity syndrome
Q87.89 Congenital contractural arachnodactyly

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.

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