TAADNEXT

TAADNextTM is a next generation sequencing (NGS) panel that analyzes 22 genes associated with thoracic aortic aneurysms and dissections (TAAD), Marfan syndrome, or related disorders.  Establishing a molecular diagnosis for these conditions can direct medical management of cardiovascular complications. This is critical to preventing aortic dissection, which is often fatal.

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TAADNextTM is a next generation sequencing (NGS) panel that analyzes 22 genes associated with thoracic aortic aneurysms and dissections (TAAD), Marfan syndrome, or related disorders.  Establishing a molecular diagnosis for these conditions can direct medical management of cardiovascular complications. This is critical to preventing aortic dissection, which is often fatal.

TAADNext detects mutations in all coding domains and splice junctions of: ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MED12, MYH11, MYLK, NOTCH1, PLOD1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, and TGFBR2.  Gross deletion/duplication analysis is performed for 17 genes (all except CBS, COL5A1, FLNA, SMAD4, and TGFB3). TAADNext identifies >96% of described mutations in these genes, when present (analytic sensitivity).

Disease Name 
Arterial tortuosity syndrome
Congenital contractural arachnodactyly (CCA or Beals syndrome)
Homocystinuria caused by cystathionine beta-synthase deficiency
Ehlers-Danlos syndrome, vascular type (EDS IV)
Ehlers-Danlos syndrome, classic type (EDS I and II)
Ehlers-Danlos syndrome, kyphoscoliosis form (EDS VI)
Juvenile polyposis/Hereditary hemorrhagic telangiectasia syndrome (JPHT)
Loeys-Dietz syndrome, types 1-5
Lujan-Fryns syndrome
Marfan syndrome
Shprintzen-Goldberg syndrome
Familial thoracic aortic aneurysm and dissection (TAAD)
X-linked periventricular nodular heterotopia, EDS variant
Disease Information 

Marfan syndrome (MFS) is an autosomal dominant multi-system disorder characterized by cardiovascular, skeletal and ocular findings.1 Diagnosis of MFS or Marfan-like syndromes can be challenging due to phenotypic variability even within a family, phenotypic overlap with clinically related disorders, and age-dependent symptoms that can manifest as early as childhood and appear over time.

One of the major features of MFS and the majority of Marfan-related disorders is an increased risk for abdominal and thoracic aortic aneurysm and dissections (TAAD), which, if untreated, have a high morbidity and mortality rate.1,2 Approximately 13,000 Americans die each year from aortic aneurysms.3  Identifying individuals at risk for TAAD is complicated by the fact that sudden death is often the first major clinical sign.  

Some conditions overlap phenotypically with MFS, but do not include the same level of risk for TAAD. These include Shprintzen-Goldberg syndrome, homocystinuria, and congenital contractural arachnodactyly (or Beals syndrome).  MFS is the most common inherited form of syndromic TAAD that occurs, along with a wide range of clinical abnormalities across various body systems. Other syndromic TAAD conditions include Marfan-like syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome (EDS), arterial tortuosity syndrome, and Lujan-Fryns syndrome.

Familial non-syndromic TAAD is characterized by aneurysms without the presence of other clinical manifestations, and typically follows an autosomal dominant pattern of inheritance. Up to 20% of individuals with TAAD have a first-degree relative with thoracic aortic disease.  Several genes have been associated with familial non-syndromic TAAD, including ACTA2, MYH11, MYLK, and PRKG1. NOTCH1 causes familial bicuspid aortic valves and other aortic valve abnormalities, which leads to an increased risk for TAAD. Sporadic forms of TAAD have also been reported.

GENE DISORDER INHERITANCE
ACTA2 TAAD Autosomal dominant
CBS Homocystinuria caused by cystathionine beta-synthase deficiency Autosomal recessive
COL3A1 Ehlers-Danlos vascular type (EDS IV) Autosomal dominant
COL5A1 Ehlers-Danlos classic type (EDS I and II) Autosomal dominant
COL5A2 Ehlers-Danlos classic type (EDS I) Autosomal dominant
FBN1 Marfan syndrome Autosomal dominant
FBN2 Congenital contractural arachnodactyly (CCA or Beals syndrome) Autosomal dominant
FLNA X-linked periventricular nodular heterotopia, EDS variant X-linked
MED12 Lujan-Fryns syndrome X-linked
MYH11 TAAD Autosomal dominant
MYLK TAAD Autosomal dominant
NOTCH1 Aortic valve disease; bicuspid aortic valve Autosomal dominant
PLOD1 Ehlers-Danlos kyphoscoliosis form (EDS VI) Autosomal recessive
PRKG1 TAAD Autosomal dominant
SKI Shprintzen-Goldberg syndrome Autosomal dominant
SLC2A10 Arterial tortuosity syndrome Autosomal recessive
SMAD3 Loeys-Dietz syndrome Autosomal dominant
SMAD4 Hereditary hemorrhagic telangiectasia; juvenile polyposis syndrome; TAAD Autosomal dominant
TGFB2 Loeys-Dietz syndrome Autosomal dominant
TGFB3 TAAD; Loeys-Dietz syndrome; arrhythmogenic right ventricular dysplasia Autosomal dominant
TGFBR1 Loeys-Dietz syndrome Autosomal dominant
TGFBR2 Loeys-Dietz syndrome Autosomal dominant

 

Testing Benefits & Indication 
  • Clarify diagnosis and risk for aortic aneurysms/dissection
  • Target medical management and prevention of aortic aneurysms/dissection and other complications
  • Offer family members genetic testing (for a familial mutation) and implement medical surveillance to only those that need it
  • Reduce healthcare costs, resources, and anxiety for families
  • Indicated in patients who are clinically suspected to have MFS, Marfan syndrome-related disorders, or familial TAAD 
  • May also be considered for differential diagnosis and carrier testing for individuals with a family history, but no concrete diagnosis
Test Description 

TAADNext includes 22 genes associated with familial TAAD, Marfan syndrome (MFS), or Marfan syndrome-related disorders (listed earlier).  Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS. Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Suspect variant calls are verified by Sanger sequencing.  This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions.  Gross deletion/duplication analysis for all genes is performed utilizing a targeted chromosomal microarray (excluding CBS, COL5A1, FLNA, SMAD4, and TGFB3).  

Mutation Detection Rate 

Up to 93% of patients with Marfan syndrome have a mutation in the FBN1 gene.5 >95% of patients with EDS type IV have a mutation in the COL3A1 gene.6 30-40% of patients with familial TAAD have a mutation in one of the TAADNext genes (clinical sensitivity).2  Many of these genes have very recently been identified, so this detection rate may increase as studies continue.  TAADNext can detect >99.9% of described mutations in the included genes, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Prenatal testing is not available.  Ambry’s prior approval is not required to test minors with a clinical suspicion or family history of TAAD.

Turnaround Time 
TEST CODE TECHNIQUE TURNAROUND TIME
8789 TAADNext 2-4 weeks
8781 FBN1 gene sequence and deletion/duplication analysis 2-4 weeks
8783 FBN1 reflex to TAADNext
Step 1: FBN1 gene sequence and deletion/duplication analysis
Step 2: TAADNext
3-5 weeks
 
8790 COL3A1 gene sequence and deletion/duplication analysis 2-4 weeks
8791 COL3A1 reflex to TAADNext
Step 1: COL3A1 gene sequence and deletion/duplication analysis
Step 2: TAADNext
3-5 weeks
 
9525 CustomNext-TAAD
Up to 22 genes of your choice for Marfan syndrome, TAAD, related disorders
2-4 weeks

 

Specialty 
Genes 
ACTA2
CBS
COL3A1
COL5A1
COL5A2
FBN1
FBN2
FLNA
MED12
MYH11
MYLK
NOTCH1
PLOD1
PRKG1
SKI
SLC2A10
SMAD3
TGFB2
TGFBR1
TGFBR2
SMAD4
TGFB3
Tests 
References 

1. Dietz HC. Marfan Syndrome. 2001 Apr 18 [Updated 2014 Jun 12]. In: Pagon RA et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

2. Milewicz DM and Regalado E. Thoracic Aortic Aneurysms and Aortic Dissections. 2003 Feb 13 Updated 2012 Jan 12. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

3. Pape et al. CDC Aortic Aneurysm Fact Sheet. Circulation. 2007 116(10):1120-7.

4. McBride KL, et al.  NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling  Hum. Mol. Genet. (2008) 17 (18): 2886-2893.

5. Korkko J, et al. Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. J Med Genet. 2002;39:34–41.

6. Pepin MG and Byers PH. Ehlers-Danlos Syndrome Type IV. 1999 Sep 2 [Updated 2011 May 3]. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.