GeneSeq®: Cardio Familial Aortopathy Profile

CPT: 81405(x3); 81408(x2); 81479
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Test Details

Test Includes

This test covers all coding nucleotides of six genes: ACTA2, COL3A1, FBN1, MYH11, TGFBR1, TGFBR2, plus at least two and typically 10 flanking intronic nucleotides upstream and downstream of each coding exon, covering the conserved donor and acceptor splice sites, as well as typically 10 flanking nucleotides in the 5′ and 3′ UTR.

Use

Confirm a clinical diagnosis of Aortopathy and identify presymptomatic family members, guiding prophylactic measures.

Limitations

This analysis does not rule out germline mosaicism, the presence of large chromosomal aberrations (including deletions, insertions, and rearrangements), mutations in regions or genes not included in this test, and possible inter/intragenic interactions between sequence variants. False-positive or false-negative results may occur for reasons that include genetic variants, blood transfusions, bone marrow transplantation, mislabeled specimens, or erroneous representation of family relationships.

Methodology

Mutation analysis is performed using the Agilent Sure Select XT® enrichment method and the Illumina® next-generation sequencing platform. Regions of interest include all exons and splice junctions for each gene and limited regions for the following: SHOC2 (exon 2), APOB (556bp of exon 26), and AKAP9 (exon 18). Sequencing reads are aligned with the hg19 build of the human genome reference sequence. Analytical sensitivity is based on the depth of coverage across the regions of interest and is provided separately for each gene. Greater than 98% of target bases are synonymous variants not previously recorded at ≥20x coverage. Sanger sequencing is used to confirm mutation identity and analyze regions with low coverage. Variants are reported using numbering and nomenclature recommended by the Human Genome Variation Society (HGVS). Variants known to be benign and synonymous variants not previously recorded in our internal variant data bases are not reported.

Additional Information

Aortopathy is characterized by aortic dilation, which can lead to life-threatening aneurysms and/or dissections. Thoracic aortic aneurysm and dissection (TAAD) may be seen in the context of several multisystem syndromes with overlapping symptoms, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and vascular-type Ehlers-Danlos syndromes (vt-EDS), but it can also occur in isolation. The genetic mutations responsible for syndromic forms of aortopathy and TAAD are known. They typically show autosomal dominant inheritance; however, a family history may not always be clear, since type, severity, and age of onset of symptoms can vary even within families. In addition, MFS, vt-EDS, and LDS may be caused by de novo mutations.

Genetic testing for familial aortopathy may:

• Confirm a clinical diagnosis of Marfan syndrome, Loeys-Dietz syndrome, vascular-type Ehlers-Danlos syndrome, or TAAD.

• Identify close relatives of an index patient who carry the mutation and are thus at high risk for TAAD and may require continual screening and lifestyle adjustments.

• In some cases, predict the severity of disease based on the exact mutation found.

Specimen Requirements

Specimen

Whole blood

Volume

10 mL whole blood or 30 mL if ordering multiple tests

Container

Yellow-top (ACD) tube or lavender-top (EDTA) tube

Storage Instructions

Maintain specimen at room temperature.

Causes for Rejection

Frozen specimen; container broken or leaking; container not labeled or label not legible; improper anticoagulant

Clinical Information

Special Instructions

Test orders must include an attestation that the provider has the patient's informed consent for genetic testing. See sample physician office consent form (Consent for Genetic Testing) in Related Documents. Please call customer service at 866-647-0735 before submitting specimens for family testing (ie, known mutations).

References

Albornoz G, Coady MA, Roberts M, et al. Familial thoracic aortic aneurysms and dissections—incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg. 2006 Oct; 82(4):1400-1405. 16996941
Comeglio P, Johnson P, Arno G, et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep; 28(9):928. 17657824
Dietz H. Marfan syndrome. [GeneReviews Web site]. December 1, 2011. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=marfan. Accessed May 18, 2012.
Judge DP. Dietz HC. Therapy of Marfan syndrome. Annu Rev Med. 2008; 59:43-59. 17845137
Loeys BL, Dietz HC. Loeys-Dietz syndrome. [GeneReviews Web site]. April 29, 2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=loeys-diets. Accessed May 18, 2012.
Milewicz DM, Regalado E. Thoracic aortic aneurysms and aortic dissections. [GeneReviews Web site]. January 12, 2012. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=taa. Accessed May 29, 2012.
Pepin MG, Byers PH. Ehlers-Danlos syndrome type IV. [GeneReview Web site]. May 3, 2011. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=eds4. Accessed May 29, 2012.

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
451432 GeneSeq: Familial Aortopathy 451331 Specimen Type: 31208-2
451432 GeneSeq: Familial Aortopathy 451417 Results: 48003-8
451432 GeneSeq: Familial Aortopathy 451429 Key Findings 53037-8
451432 GeneSeq: Familial Aortopathy 451431 Additional Information 49549-9
451432 GeneSeq: Familial Aortopathy 451433 Gene Information 51968-6
451432 GeneSeq: Familial Aortopathy 451434 Tech Spec Results 51958-7
451432 GeneSeq: Familial Aortopathy 451435 Seq Variants Detected 69548-6
451432 GeneSeq: Familial Aortopathy 451409 Disclaimer N/A
451432 GeneSeq: Familial Aortopathy 451436 Director Review: 48672-0
451432 GeneSeq: Familial Aortopathy 451437 PDF 51969-4
451432 GeneSeq: Familial Aortopathy 451415 GeneSeq: Familial Aortopathy N/A

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