Molecular Genetics Genetic Aortopathy and Arteriopathy Panel

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Test Code:

1490
Department:

Molecular Genetics
Test Synonyms:

GAAP
CPT Code(s):

81410

Background:

Genetic aortopathy is defined as aortic disease in patients who have confirmed family history of aortic dissection, aortic aneurysm, or sudden unexpected death of an unknown cause. This can present as either an isolated finding (non-syndromic) or part of a larger syndrome (syndromic Both non-syndromic and syndromic genetic aortopathies can impact a broad spectrum of protein functions including the extra-cellular matrix, vascular smooth muscle cell contraction and transforming growth factor-β signaling pathways, among others. There is considerable overlap between syndromic and non-syndromic aortopathy complicating the ability to accurately diagnose based on clinical features alone-particularly if additional symptoms of a syndrome have not yet manifested. Therefore, a comprehensive multigene panel is recommended as the first step in the genetic testing strategy.

This next-generation sequencing test includes genes associated with Thoracic Aortic Aneurysms and Aortic Dissections (TAAD), Marfan syndrome, Loeys-Dietz syndrome, and Ehlers-Danlos syndrome, among others. Specifically, this test is designed to detect clinically significant variants in the coding region of 84 genes associated with familial aneurysm and aortopathy. Additionally, this test can detect large copy number variants in the following regions 7q11.23 (ELN) and 16p13 (MYH11) (see methodology below).

This test was developed in collaboration with the OHSU Northwest Genetic Aortopathy & Arteriopathy Program (NW GAAP) team. For clinical consultation—including with Dr. Sherene Shalhub, Division Head of OHSU Vascular and Endovascular Surgery and a leading expert in the medical and surgical management of genetic aortopathies and arteriopathies—please contact the team via email at [email protected] or by phone at 503-494-7593.

Reasons for Referral:

Aortic or arterial aneurysms and/or dissections at an age younger than 60 years.
Clinical presentation consistent with Marfan syndrome, Loeys-Dietz Syndrome, or Vascular Ehlers-Danlos Syndrome or other genetic aortopathies.
Positive family history for aneurysms and/or dissections (targeted testing is available if familial variant is known).
Carrier testing (targeted testing is available if familial variant is known).

Methodology:

Genomic DNA is analyzed using next-generation sequencing (NGS) on the Illumina NextSeq 2000 platform, with target enrichment performed using hybridization-based probes to capture exonic (coding) regions of the gene(s). Single nucleotide variants (SNVs) and small insertions or deletions (INDELs) are identified using the Illumina DRAGEN Enrichment Workflow, executed onboard the NextSeq2000. This pipeline combines software and hardware acceleration to generate high-confidence germline haplotype calls. Clinical and analytical validation of DRAGEN was performed in our laboratory. Based on validation study results, for SNVs, this assay achieves >96% analytical sensitivity and >99% positive predictive value (PPV). For INDELs <50 bp, the analytical sensitivity is >87% and the PPV is >97%. INDELs >50 bp may be detected but the sensitivity for these is reduced.

Exon-level copy number variants (CNVs) are detected using the Germline Copy Number Variation Best Practices pipeline from GATK. A Bayesian model, clinically validated in our laboratory, enables detection of deletions and duplications involving three or more contiguous exons in genes with adequate probe coverage and without complicating factors (e.g. pseudogene homology, short tandem repeats, segmenral duplications). Please note that exon-centric microarray remains the gold standard for exonic copy number variant calling. If exon-centric microarray is of interest, please contact the laboratory for additional information.

This test is not designed to detect polynucleotide repeats, low-level mosaicism, structural rearrangements or balanced alterations (e.g. inversions, gene conversion events, translocations, etc.) or variants in difficult regions. Additionally, variants located in regions of insufficient coverage, including introns and promoter regions; pseudogenes; where the reference genome is inaccurate or contains gaps and insertions; and of high GC content may not be detected. This test does not provide complete coverage of all exons and noncoding regions may have limited information and ability to interpret. Variants in introns that are greater than 10 bp from the intron-exon junction may be analyzed. Please contact the laboratory if interrogation of intronic sequence greater than 10 bp from the intron-exon boundary is desired.

Genetic Aortopathy and Arteriopathy Panel (84 genes)

ABCC6, ABL1, ACTA2, ADAMTS2, ADAMTS10, ADAMTS17, ADAMTSL4, ADAMTSL6 (THSD4), AEBP1, ALDH18A1, ATP6V0A2, ATP6V1A, ATP6V1E1, B3GALT6, B4GALT7, B3GAT3, BGN, CBS, CHST14, COL1A1, COL1A2, COL2A1, COL3A1, COL4A1, COL4A2, COL5A1, COL5A2, COL9A1, COL9A2, COL9A3, COL11A1, COL11A2, DCHS1, DSE, DZIP1, EFEMP2/FBLN4, ELN, EMILIN1, ENPP1, FBLN5, FBN1, FBN2, FKBP14, FLCN, FLNA, FOXE3, GATA5, GGCX, HGD, HOXA1, KCNJ2, LOX, LTBP2, LTBP3, LTBP4, MED12, MFAP5, MYH11, MYLK, NKAP, NOTCH1, PLOD1, PLOD3, PRDM5, PRKG1, PYCR1, RIN2, SKI, SLC2A10, SMAD2, SMAD3, SMAD4, SMAD6, SOX18, TAB2, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, THBS2, UPF3B, XYLT1, ZNF469

For a comprehensive list of regions with limited coverage on this panel, please refer to the following table.

Specimen Requirements:

Blood: EDTA or ACD (Solution A or B):

Adult: 5 mL
Child: 5 mL
Infant: 2-3 mL

Saliva: 2 ORAgene™ Saliva Collection Kits (OGR-500) used according to manufacturer instructions. Please contact KDL Client Services for a Saliva Collection Kit for patients that cannot provide a blood sample.

Assisted Saliva: 4 ORAgene™ Assisted Saliva Collection Kits (OGR-575) used according to manufacturer instructions. Please contact KDL Client Services for an Assisted Saliva Collection Kit for patients that cannot provide a blood sample.

Buccal Cells: 4 CytoSoft™ Cytology Brush (Medical Packaging CYB-1) used according to manufacturer instructions. Please contact KDL Client Services for a Buccal Collection Kit for patients that cannot provide a blood sample.

Skin Fibroblast: Punch Biopsy (Cell cultures will be prepared at KDL and used for testing) or 2 T-25 confluent flasks.

DNA: 5-10µg at a minimum of 60-100ng/µL (DNA must be extracted in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or CMS).

For routine testing of blood and saliva (or DNA extracted from them), KDL does NOT accept samples from patients within two (2) weeks of a packed cell/platelet transfusion or within four (4) weeks of a whole blood transfusion. In exceptional cases where testing is required within these timeframes, please contact our laboratory for guidance.

A REQUISITION FORM MUST ACCOMPANY ALL SAMPLES. Please include detailed clinical information, including ethnicity, clinical history, and family history.

Test Performed (Days):

Weekly

Turn Around Time:

3-5 weeks

Shipment Sensitivity Requirements: